Tetrafluorophenethylaralkylamine compounds

ABSTRACT

New fluoro derivatives of aralkylamine compounds, particularly 2-(2-phenyl-1,1,2,2-tetrafluoroethyl)benzylamine, as well as the N-alkyl and the N,N-dialkyl derivatives thereof are prepared by reaction of 2-bromobenzonitrile with benzylmagnesium chloride to produce 2&#39;-bromo-2-phenylacetophenone; oxidation of said acetophenone with selenous acid to produce 2-bromobenzil; conversion of the benzil compound by treatment with sulfur tetrafluoride to the corresponding 2-bromo-α ,α-α&#39;,α&#39;-tetrafluorobibenzyl; followed by reaction of the 2-bromobibenzyl compound with a metal cyanide to produce the corresponding 2-(2-phenyl-1,1,2,2-tetrafluoroethyl)benzonitrile. This nitrile compound is then reduced with lithium aluminum hydride to produce the corresponding benzylamine, which is then converted, if desired, to the N-alkyl and/or N,N-dialkyl 2-(2-phenyl-1,1,2,2-tetrafluoroethyl)benzylamine. Alternatively, the nitrile or the precursor bromobibenzyl can be converted by Grignard reactions to the corresponding α-alkyl or α,α-dialkylbenzylamine which can then be converted if desired to the corresponding N-alkyl and/or N,N-dialkyl substituted benzylamine compound. The phenyltetrafluoroethylbenzylamine as well as its N-alkyl and N,N-dialkyl derivatives are active as antiarrhythmic agents.

This application is a division of copending U.S. Application Ser. No.102,130 filed Dec. 28, 1970, now U.S. Pat. No. 3,812,177 which in turnis a continuation-in-part of U.S. Application Ser. No. 799,945 filedFeb. 2, 1969 and now abandoned, which in turn is a continuation-in-partof application Ser. No. 712,616 filed Mar. 13, 1968 and now abandoned.

This invention relates to fluoro derivatives of aralkylamine compounds.More specifically, it relates to perfluoroalkylaralkylamines containingan additional homocyclic or heterocylic ring and the correspondingN-substituted derivatives such as the N-alkyl and N,N-dialkylderivatives thereof.

This invention also relates to the novel processes and the novelintermediates utilized in the production of newperfluoroalkylaralkylamines, to pharmaceutical formulations of the newaralkylamines and to methods of treating or preventing cardiacarrhythmias using the novel compounds and/or pharmaceutical formulationsthereof, described hereinafter.

The new compounds of our invention are terminally disubstitutedperfluoroalkane compounds in which one of the two terminal substituentsis an aromatic ring having at least one of its hydrogens replaced by astraight or branched chain aminoalkyl radical or an amino heterocyclicradical and in which the other terminal substituent is a homocyclic orheterocyclic ring selected from aryl, substituted aryl, heterocyclic andsubstituted heterocyclic substituents. The compounds of our inventionare represented structurally as follows: ##SPC1##

In which n is an integer varying from 2 to 4 inclusive; A is asubstitued or unsubstituted homocyclic or heterocyclic ring of from 5 to6 atoms, such as an aromatic ring, a heteroaromatic ring or a partiallyor completely reduced aromatic or heteroaromatic ring; and B is an aminosubstituted straight or branched chain aliphatic or heterocyclic sidechain containing from 1 to 8 carbon atoms which is connected to thebenzenoid ring by one or more carbon-carbon bonds.

A preferred class of compounds of our invention are theaminoalkylarylperfluoroalkanes represented structurally by the formula##SPC2##

in which n is an integer varying from 2 to 4 inclusive; m is an integervarying from 1 to 4 inclusive; one or more of the methylene (CH₂)hydrogens may be replaced by a lower alkyl (1-4 carbon atoms)substituent; R₂ and R₃ are either similar or dissimilar and are eitherhydrogen, alkyl (preferably of from 1 to 6 carbon atoms), alkenyl oralkynyl, and can be joined together or alternatively may be linked tothe aromatic ring or to one of the methylene substituents linking thearomatic ring and the amine radical to form a heterocyclic ring of from5 to 6 atoms such as imidazolinyl, piperidyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, or loweralkyl piperazinyl and A is aryl, especiallyphenyl or substituted phenyl, heterocyclic aromatic or a partially orcompletely reduced derivative thereof.

Also included within the scope of our invention are derivatives ofcompounds having the above formula in which one or more of the arylheterocyclic rings or one of the reduced derivatives is furthersubstituted. A preferred group of such compounds includes derivatives inwhich one or more of the hydrogens of the phenyl ring and/or one or moreof the hydrogens of the ring represented by A is replaced bysubstituents selected from the group consisting of hydrogen, an alkylgroup having up to 6 carbon atoms, an alkenyl group having up to 6carbon atoms, a perfluoroalkyl group having up to 4 carbon atoms, aphenyl or a substituted phenyl radical, an acyl group having up to 4carbon atoms, a perfluoroacyl group having up to 4 carbon atoms, amino,an alkylamino group having up to 4 carbon atoms, an alkylaminoalkylgroup having up to 8 carbon atoms, a dialkylamino group having up to 8carbon atoms, a dialkylaminoalkyl group having up to 10 carbon atoms, anacylamino group having up to 4 carbon atoms, a perfluoroacylamino grouphaving up to 4 carbon atoms, an alkylsulfonylamino group having up to 4carbon atoms, halogen (fluorine, chlorine, bromine, or iodine),hydroxyl, an alkoxyl group having up to 4 carbon atoms, aperfluoroalkoxyl group having up to 4 carbon atoms, cyano, carboxy,carboamoyl, an alkylcarbamoyl group having up to 5 carbon atoms, adialkylcarbamoyl group having up to 9 carbon atoms, a carbalkoxy grouphaving up to 6 carbon atoms, mercapto, an alkylmercapto group having upto 4 carbon atoms, a perfluoroalkylmercapto group having up to 4 carbonatoms, an alkylsulfonyl group having up to 4 carbon atoms, aperfluoroalkylsulfonyl group having up to 4 carbon atoms, sulfamoyl, analkylsulfamoyl group having up to 4 carbon atoms, or a dialkylsulfamoylgroup having up to 8 carbon atoms. More than one of these substituentsmay be on each ring.

An especially preferred group of compounds included within the scope ofour invention is represented by the formula ##SPC3##

or derivatives of these compounds in which one or more of the methylene(CH₂) hydrogens is replaced by a lower alkyl (of from 1 to 4 carbonatoms) substituent, in which R₂ and R₃ are either hydrogen, alkyl(preferably of from 1 to 6 carbon atoms), alkenyl, alkynyl, and can bejoined together through an atom of nitrogen, oxygen or sulfur to form aheterocyclic ring of from 5-6 atoms (such as 1-piperidyl,1-pyrrolidinyl, 4-morpholinyl, 4-thiomorpholinyl or1-loweralkyl-4-piperazinyl).

Illustrative of the compounds included within the scope of the inventionare 2-(2-phenyl-1,1,2,2-tetrafluoroethyl)benzylamine,α-methyl-2-(2-phenyl-1,1,2,2-tetrafluoroethyl)benzylamine,α,α-dimethyl-4-(2-phenyl-1,1,2,2-tetrafluoroethyl)benzylamine,α-methyl-4-(2-phenyl-1,1,2,2-tetrafluoroethyl)benzylamine, thecorresponding secondary amines as, for example, the N-methyl, N-ethyl,N-propyl, N-allyl, N-propargyl, N-isopropyl, N-butyl, N-t-butyl, N-amyland the N-acyl derivates thereof, as well as the correspondingN,N-disubstituted derivatives, especially the N,N-dialkyl derivatives,thereof.

The compounds represented above, in either their free base or salt form,possess useful pharmacological properties. In particular, they have beenfound to possess antiarrhythmic activity. It has been found that theadministration of compounds of the present invention, depicted in theabove formula, results in the prevention of arrhythmia in animals underconditions which ordinarily cause the development of arrhythmia in theanimal 100% of the time.

It has further been found that administration of the compounds of thepresent invention will arrest an existing arrhythmia in the animal beingtreated and cause a resumption of normal cardiac rhythm. Asantiarrhythmic agents, these compounds may be administered orally orparenterally. The formulations for administration may be prepared inconventional manner, employing conventional pharmaceutical carriers andexcipients.

The non-toxic acid addition salts useful as components in thecompositions provided by the present invention are salts formed by thereaction of an equivalent amount of the amine compound of the aboveformula and an acid which is pharmacologically acceptable in theintended doses. Salts of the above compound which are useful are saltsof the amine with hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methanesulfoniic acid, isethionic acid, fumaric acid,propionic acid, lactic acid, gluconic acid, maleic acid, succinic acid,tartaric acid, and the like. The salts of the compounds of thisinvention are prepared for convenience in preparing pharmaceuticalformulations. The pharmacological action of the salts is considered tobe the same as the chemically equivalent quantity of the bases.

The daily doses are based on the total body weight of the test animaland vary between about 1.00 and 100.00 mg./kg. Thus, a unit dose basedon four-times-a-day administration is between 2.5 mg. and 250 mg. for a10 kg. dog, and a total daily dose for a 10 kg. dog would vary betweenabout 10 mg. and 1,000 mg. For larger animals, proportional dosages areemployed, based on the weight of the animal. Suitable dosage formsprovided for the administration of the compositions used in the methodof the invention are tablets, capsules (which may be suitably formulatedfor either immediate or sustained release), syrups, elixirs, parenteralsolutions, and the like. These dosage forms preferably contain per unitone or more multiples of the desired dosage unit in combination with thepharmaceutically acceptable diluent or carrier required for preparingthe dosage unit.

The compounds represented by the above structural formulas may beprepared as illustrated below.

FLOW SHEET I ##SPC4##

wherein

R₁ is hydrogen or lower alkyl (preferably of from 1-5 carbon atoms) oramino substituted lower

R_(r) ₂ and R₃ can be similar or dissimilar and are either hydrogen,alkyl (preferably of from 1-6 carbon atoms), aralkyl (preferably benzylor phenethyl), alkenyl, alkynyl, and can be joined together or with oneof the methylene carbons linking the amine substituent and the phenylring or through an atom of nitrogen, oxygen or sulfur to form aheterocyclic ring of from 5-6 atoms (such as imidazolinyl, piperidyl,pyrrolidinyl, morpholinyl, thiomorpholinyl or loweralkyl piperazinyl);

X and X' are selected from the group consisting of hydrogen, halogen(chlorine or fluorine), alkyl (preferably of from 1-6 carbon atoms),alkoxy, (preferably of from 1-5 carbon atoms), perfluoroalkyl (e.g.,trifluoromethyl), alkylmercapto (preferably of from 1-6 carbon atoms),alkylsulfonyl (preferably of from 1-6 carbon atoms), anddialkylsulfamoyl (preferably of from 2-8 carbon atoms);

Hal is a halogen selected from the group consisting of bromine oriodine;

n is an integer selected from the group consisting of 2 and 3;

m is an integer selected from the group consisting of 1 to 4 inclusive;

Alk is alkyl (preferably lower alkyl of from 1-6 carbon atoms); and

A is an aromatic ring such as phenyl, a cycloaliphatic ring, aheterocyclicaromatic ring of 5 or 6 atoms or a partially reduced orcompletely reduced heterocyclic ring including preferably pyridine,pyrimidine, thiazole, thiophene, imidazole, oxazole and partially orcompletely hydrogenated derivatives thereof.

In accordance with the process of our invention, the di- or triketoneCompound I is treated with sulfur tetrafluoride to convert the diketo ortriketo compound to the corresponding diarylperfluoroalkyl compound as,for example, 2-bromo-α,α,α',α'-tetrafluorobibenzyl, or1-(2-bromophenyl)-1,1,2,2,3,3-hexafluoro-3-phenylpropane. Thisconversion to the perfluoro compound is preferably carried out atelevated temperatures by mixing the di- or triketone with an excess ofsulfur tetrafluoride and catalytic amounts of a Lewis acid such ashydrogen fluoride, boron trifluoride and the like.

The sulfur tetrafluoride employed in the reaction is either purifiedprior to addition to the reaction mixture by shaking in contact with asmall amount of mercury or by adding the mercury directly to thereaction mixture.

The amount of mercury employed is not critical but it is preferred toemploy at least about 1 gram of mercury/100 g. of sulfur tetrafluorideto remove undesirable contaminants such as sulfur chloride. Preferably,the sulfur tetrafluoride is treated in situ by the direct addition ofmercury to the mixture containing sulfur tetrafluoride and di- ortriketone.

The temperature of the reaction mixture is not critical but ispreferably maintained between 50° and 200°C. The perfluoro compound isreadily obtained from the reaction mixture by extraction with solventssuch as benzene, toluene, methylene chloride, chloroform, or the like,and evaporation of the solvent to yield the compound as a residualsolid.

The thus-obtained phenylperfluoroalkylbromo benzene is converted intothe correspondingly substituted benzonitrile by reaction of thesubstituted compound with a metal cyanide such as cuprous cyanide andsuitable anhydrous nonhydroxylic solvents such as acetonitrile,dimethylformamide, quinoline or pyridine to produce the correspondingbenzonitrile. The preferred solvent is quinoline containing a smallamount of dimethylformamide. The temperature at which the reaction iscarried out is not critical but it is preferred to employ elevatedtemperatures in the range of 100°-200° C. The desired product is readilyrecovered employing conventional techniques to remove the metal saltswhich precipitate from the reaction mixture, followed by filtration,evaporation of the solvent, if desired, followed by crystallization.

The thus-obtained phenylperfluoroalkylbenzonitrile is then reduced toproduce the corresponding benzylamine, e.g.2-(2-phenyl-1,1,2,2-tetrafluoroethyl) or4-(3-phenyl-1,1,2,2,3,3-hexafluoropropyl)benzylamine. The reduction isreadily effected by contacting the benzonitrile compound with lithiumaluminum hydride in the presence of a suitable inert organic solvent,such as tetrahydrofuran, ether or other solvents conventionally employedwith lithium aluminum hydride. Preferably, this reduction is carried outin the presence of aluminum chloride and an ether compatible withaluminum chloride as a solvent. The temperature at which the reductionis carried out is not critical but it is preferred to employ ambienttemperatures and a range of from 0°-50°C. is satisfactory. The resultingbenzylamine compound is readily recovered employing conventionaltechniques.

In preparing higher homologs of the benzylamine compound, theintermediate phenylperfluoroalkylaryl nitrile is converted usingconventional reaction methods to produce the desired compounds. Thus,the intermediate phenylprefluoroalkylbenzonitrile is hydrolyzed to thecorresponding benzoic acid. The thus-obtained acid is then reduced usinglithium aluminum hydride to produce the corresponding benzyl alcoholwhich is recovered in accordance with conventional procedures andtreated with a hydrogen halide such as aqueous hydrogen bromide toproduce the corresponding benzyl halide. The thus-obtained product ispurified using conventional techniques and subjected to treatment withpotassium cyanide thereby completing the conversion of the startingbenzonitrile to the next higher homolog, the phenylperfluoroalkylphenylacetonitrile.

The corresponding N-(phenylperflouroalkylbenzyl)formamide (V) or higherhomologs thereof in which R₁ is hydrogen, is prepared by formylation ofthe aralkylamine e.g. benzylamine compound (IV) employing conventionalconditions and reagents such as formic acid or esters thereof for thispurpose. The resulting formamide derivative can be recovered inconventional manner. The N,N-dimethylamine (VI), wherein R₂ and R₃ eachrepresent methyl, is readily prepared by the treatment of the primaryamine compound (V) with formaldehyde and formic acid in accordance withthe known Eschweiler-Clarke modification of the Leuckart Reaction.Recovery of the N,N-dimethylamine is accomplished in conventionalmanner. The N-methylaralkylamine, e.g. the N-methylbenzylamine,represented by (VII) wherein Alk is methyl, may be prepared by eitherreduction of the corresponding N-(phenylperfluoroalkylbenzyl)formamide(V) or by mono-dealkylation of the corresponding N,N-dimethylamine (VI)wherein R₂ and R₃ each represent methyl. Reduction of theformamidomethyl derivative is effected utilizing lithium aluminumhydride under the conditions set forth above for carrying out thereduction of the corresponding benzonitrile (III). Similarly,dealkylation of the N,N-dimethylamine (VI) can be effected in knownmanner such as by treatment with cyanogen bromide followed by hydrolysisof the intermediate cyanamide or by treatment with a haloformatefollowed by hydrolysis of the resulting urethane intermediate. In eachinstance, the desired compound can be recovered employing conventionaltechniques.

The N-loweralkylamines and the N,N-diloweralkylamines corresponding tocompounds (VII) and (VI), respectively, are likewise prepared from thecorresponding primary amine (IV) by analogous reactions. Thus, theprimary amine (IV) is treated with a lower aliphatic acid halide oranhydride of from 2-5 carbon atoms, e.g., acetyl chloride, aceticanhydride, propionyl chloride, butyryl chloride or valeryl chloride toproduce the N-alkanoyl amide corresponding to (V) as, for example, theN-acetyl, N-propionyl, N-butyryl or N-valeryl amide. The thus-obtainedamide is reduced to the corresponding N-loweralkyl benzylamine compound(VI) by reduction in the manner described for the correspondingbenzonitrile compound (III), i.e., by reduction with lithium aluminumhydride. The secondary amine compounds (VII) produced in this manner arethe N-loweralkyl derivatives of 2-(phenylperfluoroalkyl)benzylamines as,for example, the N-ethyl, N-propyl, N-butyl and the N-amyl derivatives.The corresponding tertiary amines (VI), the N,N-diloweralkylderivatives, are prepared from the secondary amines by repeating theprocess employed in the preparation of the secondary amines. Thus, theamides of the secondary amines are prepared and reduced with lithiumaluminum hydride to produce the corresponding tertiary amines as, forexample, the corresponding N,N-diethyl, N-ethyl-N-methyl, N,N-dipropyl,N,N-dibutyl and the N,N-diamyl derivatives of substituted andunsubstituted phenylperfluoroalkyl benzylamine.

In accordance with an alternative process for the preparation of thecompounds of formula (VI), wherein ##STR1## represents 1-pyrrolidinyl,1-piperidyl, 4-morpholinyl, 4-thiomorpholinyl or1-loweralkyl-4-piperazinyl, the primary amine (IV) is condensed with anα,α-dihalo compound such as tetramethylene bromide, pentamethylenebromide, β,β'-dichlorodiethyl ether, β,β'-dichlorodiethyl sulfide, or anN-alkyl-β,β'-dichlorodiethyl amine.

In accordance with a further alternative process for the preparation ofthe primary, secondary, and tertiary benzylamine products of ourinvention, a bromo or iodo substituted diarylperfluoroalkyl compound(II) is converted by the process illustrated below.

FLOW SHEET II ALTERNATIVE PROCESS FOR PRIMARY, SECONDARY, OR TERTIARYBENZYLAMINE PRODUCTS CORRESPONDING TO (IV), (VI) OR (VII) ##SPC5##

wherein Hal, n, R₂, R₃, X and X' have the significance previouslyindicated.

Thus, the bromo or iodo substituted diaryl perfluoroalkyl compound (II)is treated with magnesium under anhydrous conditions to form theGrignard reagent (IIA) which, in turn, is treated with carbon dioxide,followed by acidic hydrolysis to produce the corresponding carboxylicacid (IIB) wherein the bromo or iodo substituent is replaced by acarboxyl group. The thus-obtained acid is then reduced using lithiumaluminum hydride to produce the corresponding benzyl alcohol (IIC) whichis recovered in accordance with conventional procedures and treated withan acid halide such as thionyl chloride, thionyl bromide, and the like,to produce the corresponding benzyl halide compound (IID) which, onreaction with ammonia or an amine, produces the corresponding primary,secondary or tertiary amine (IIE) which is recovered employingconventional techniques. In this manner, there is produced in additionto the N-alkyl and N,N-dialkyl derivatives of the substituted andunsubstituted phenylperfluoroalkylbenzylamines or higher homologsthereof enumerated hereinabove, the corresponding compounds in which theamine nitrogen forms a part of a heterocyclic ring such as a piperidyl,pyrrolidinyl, morpholinyl, thiomorpholinyl or 1-loweralkyl-4-piperazinylring.

The benzyl halide (IID) is alternatively prepared from alkylatedtetrafluorobibenzyl compounds, e.g.2,3-dimethyl-α,α,α',α'-tetrafluorobibenzyl by selective bromination ofthe alkyl substituent using the appropriate molar amount of anN-bromoimide, e.g. N-bromo succinimide, to produce the desiredsubstituted benzyl bromide. There can be one or more alkyl substituentspresent in the aromatic ring and by selection of the proper molar amountof the N-bromoamide the compound produced will have one or more of thealkyl substituents substituted by bromine with resultant production ofthe desired benzyl bromide compound. The bromine substituent is thenreplaced by the desired amine function by any of a number of knownmethods for converting benzyl bromides to the corresponding benzyl amineor substituted amine. Thus, the obtained benzyl bromide compound iscontacted with hexamethylene tetramine to produce the correspondinghexaminium bromide compound which on reaction with concentratedhydrochloric acid yields the desired benzyl amine. Alternately, thebenzyl bromide compound is reacted with potassium phthalimide to producethe corresponding phthalimide derivative which on acid hydrolysis orreaction with hydrazine yields the desired benzylamine.

The perfluoroalkylaralkylamines in which the amine nitrogen is attachedto a branched chain aliphatic side chain are readily prepared by thereaction of the appropriately substituted nitrile III with a lower alkylmagnesium halide, e.g. methyl magnesium bromide, to produce anintermediate imine followed by lithium aluminum hydride reduction of theimine to produce the corresponding branched chain primary amine whereinthe alkyl substituent is attached to the carbon immediately adjacent tothe amino substituent. For example, when2-(α,α,β,β-tetrafluorophenethyl)benzonitrile is treated in turn withmethyl magnesium bromide to produce the intermediate ketimine followedby reduction with lithium aluminum hydride, the product produced isα-methyl-2-(α,α,β,β-tetrafluorophenethyl)benzylamine. When the startingbenzonitrile is replaced by the homologous2-(α,α,β,β-tetrafluorophenethyl)phenylacetonitrile, the productsobtained following ketimine formation with the appropriate Grignardreagent and lithium aluminum hydride reduction are respectively theα-methyl, α-ethyl, and α-propyl derivatives of2-(α,α,β,β-tetrafluorophenethyl)phenethylamine.

In an alternate method of producing such α-alkyl substitutedbenzylamines, the benzonitrile III is converted by reaction with aloweralkyl Grignard reagent, e.g., methyl, ethyl, propyl or butylmagnesium bromide, to the Grignard adduct followed by acidic hydrolysisto produce the 4'-(α,α,β,β-tetrafluorophenethyl)-acetophenone compound.The acetophenone compound is then converted in conventional manner tothe corresponding oxime which in turn is catalytically hydrogenated toproduce the desired α-alkyl substituted benzylamine compound.

In addition to theα-alkyl-2-(α,α,β,β-tetrafluorophenethyl)-phenethylamine compounds, thecorresponding α,α-disubstituted, i.e., dialkyl compounds are prepared byprocesses starting from a bromo or iodo substituted diarylperfluoroalkyl compound II hereinabove in which Hal is bromo or iodine.The compounds prepared in accordance with the following processes are,for example, the α,α-dimethyl, α,α-diethyl, α,α-dipropyl,α-methyl-α-ethyl, α-methyl-α-propyl, α-ethyl-α-propyl, α-methyl-α-butyl,and α-methyl-α-isopropyl (α,α,β,β-tetrafluorophenethyl)benzylamine. Thecorresponding N-alkyl or N,N-dialkyl derivatives thereof, e.g., theN-methyl, N-ethyl, N-propyl, N-butyl, N,N-dimethyl, N,N-diethyl,N,N-dipropyl, N-methyl-N-ethyl, N-methyl-N-propyl, N-methyl-N-butyl andN-ethyl-N-propyl derivatives are prepared by methods described in thepreceding pages for converting the benzylamine into the correspondingN-alkyl or N,N-dialkyl derivatives.

In the process outlined below, for producing ##SPC6##

the α,α-dialkyl substituted benzylamine compounds, a 3 or 4 bromosubstituted diaryl perfluoroalkyl compound is treated with magnesiumunder anhydrous conditions to form the Grignard reagent IIA₁ which inturn is treated with an aliphatic ketone such as acetone, diethylketone, di-N-propyl ketone or a mixed ketone as, for example,methyl-ethyl ketone, methyl-propyl ketone, methyl-butyl ketone,ethyl-propyl ketone and methyl-isopropyl ketone to produce afterhydrolysis the corresponding benzyl alcohol IIA₂ containing alkylsubstituents attached to the carbinol carbon of the benzyl alcohol.Alternatively, the 3'- or 4'-perfluoroalkylphenyl substitutedacetophenone is treated with a loweralkyl Grignard reagent to produceafter hydrolysis the α,α-dialkyl benzyl alcohol. Alternatively, Grignardreagent IIA₁ is carbonated to produce after hydrolysis the correspondingbenzoic acid. This acid is esterified and treated with a lower alkylGrignard reagent to produce after hydrolysis the α,α-dialkylbenzylalcohol. This tertiary alcohol is then employed in a Ritter reactionwhich involves treatment of the tertiary alcohol with an alkali metalcyanide in sulfuric acid or methane sufonic acid with resultantproduction of the corresponding benzyl formamide compound IIA₃, which onacid hydrolysis produces the desired α,α-dialkyl substituted benzylaminecompound.

The di- and triketones utilized as starting materials in the describedprocess are readily prepared from known materials. Thus, the diaryldiketo compounds are readily prepared by initially condensing theappropriately substituted bromobenzonitrile with a benzylmagnesiumhalide to produce the corresponding bromophenylbenzyl ketimine followedby hydrolysis under acid conditions to produce a bromo-substitutedacetophenone compound.

Alternatively, the diaryl diketo compounds are prepared by initiallycondensing the appropriately substituted benzonitrile or a nitrile of anappropriately substituted heterocyclic compound with a benzylmagnesiumhalide containing an additional bromo substituent attached to the phenylring of the benzylmagnesium halide to produce the correspondingbromophenylbenzyl ketimine or the bromophenyl heterocyclic ketiminefollowed by hydrolysis under acid conditions to producephenylacetophenone or phenacyl heterocyclic compound. As previouslyindicated, the heterocyclic portion of the molecule has a heterocyclicaromatic ring of 5 or 6 atoms selected from pyrimidine, thiazole,thiophene, imidazole and oxazole.

The thus-obtained bromophenylacetophenone or bromophenacyl heterocycliccompound is then treated with a mild oxidizing agent, such as selenousacid, to produce a bromo-substituted benzil-type compound. The oxidationreaction is carried out in an aqueous medium containing a solvent forthe bromophenylacetophenone. The solvent is preferably one which is atleast partially water-miscible. Typical examples are dioxane, aceticacid or lower aliphatic alcohols. The temperature at which the reactionis carried out is not critical but it is preferred to employ elevatedtemperatures in the range of about 50°-150°C. The desired product isreadily recovered employing conventional techniques such as byextraction with water-immiscible solvents. Solvents including benzene,xylene, toluene and the like are preferred.

The foregoing conversion is outlined in the following flow sheet.

FLOW SHEET III PREPARATION OF STARTING DIKETONE ##SPC7##

In the above formulas Hal, X and X' have the significance previouslyindicated.

The corresponding diarylpropanetrione included in formula (I) of FlowSheet I is prepared in accordance with the process of our invention asoutlined in the following flow sheet.

FLOW SHEET IV PREPARATION OF STARTING TRIKETONE ##SPC8##

in which Hal, Alk, X and X' have the significance previously indicated.

Thus, an appropriately substituted benzaldehyde is condensed with abromo or iodo substituted acetophenone in the presence of an acid oralkaline condensing agent to produce as a first intermediate asubstituted benzal acetophenone (A) which is isolated in accordance withconventional procedures and treated in a suitable solvent with anequimolar amount of bromine to produce the corresponding benzalacetophenone dibromide (B) and is isolated by conventional procedures.The dibromide is then treated with an excess of an alkali metalalkoxide, such as sodium methoxide, to produce a loweralkyl enol etherof the corresponding dibenzoyl methane compound (C). The enol ether isthen hydrolyzed under acidic conditions to produce the correspondingdibenzoyl methane compound (D). The dibenzoyl methane compound is thentreated with at least two molecular equivalents of bromine to producethe corresponding dibenzoyldibromomethane compound (E). The dibromocompound is then treated with sodium acetate and glacial acetic acid toreplace the bromo substituents with acetoxy substituents and theresulting compound is hydrolyzed with water to the desireddiarylpropanetrione monohydrate compound (F), which is converted byheating under vacuum to effect a dehydration and produce the desiredpropanetrione material utilized as starting material in the preparationof the perfluoroalkyl compounds of our invention (I).

When the starting benzaldehyde compound is replaced by a heterocyclicaldehyde such as thiophen-2-aldehyde the product obtained is a1-aryl-3-heterocyclic propanetrione compound.

The starting 2, 3 or 4-bromobenzonitriles or heterocyclic nitrilescontaining additional X substituents in the aromatic or heteroaromaticring are either known compounds or may be prepared from thecorresponding benzoic or heterocyclic carboxylic acids by conversion ofthe acid to the corresponding amide and dehydration of the amide to thedesired nitrile. The substituted benzylmagnesium halide is also readilyprepared from the corresponding benzyl halide using conventionalsynthetic procedures.

EXAMPLE 1 2'-Bromo-2-phenylacetophenone

A solution of 2-bromobenzonitrile, 12.0 g. (0.066 mole) in 80 ml. ofabsolute ether is added dropwise to a stirred solution ofbenzylmagnesium chloride prepared from 0.42 g. (0.264 g. atom) ofmagnesium turnings and 33.42 g. (0.264 mole) of benzyl chloride in 140ml. of absolute ether in a nitrogen atmosphere. The mixture is stirredat room temperature for 7 hours and allowed to stand overnight. Aftercooling in an ice-bath, the adduct is hydrolyzed by the dropwiseaddition of 100 ml. of 0.5 M citric acid. The organic phase is separatedand the aqueous phase re-extracted with several portions of coldbenzene. The combined organic layers are extracted with about 100 ml. ofice-cold 6 N hydrochloric acid in several portions. After chilling thecombined acid extracts in an ice-bath for several hours, the precipitateof 2-bromophenylbenzyl ketimine hydrochloride is collected, washed with15% ethanol in ether, then with absolute ether. After brief air-drying,the salt is recrystallized from cold methanol-ether, m.p. 176°- 181°C.

The ketimine hydrochloride, suspended in 25 ml. 0f 3N hydrochloric acid,is heated on the steam-bath for 11/2 hours. The product separates as anoil and is extracted into benzene. Evaporation of the washed and driedbenzene extract leaves the yellow oily product, N_(D) ²⁵.5.sup.° =1.6050. Anal. Calc'd. for C₁₄ H₁₁ BrO: C, 61.11; H, 4.03; Br, 29.04.Found: C, 61.17; H, 3.97; Br, 28.99.

EXAMPLE 2 2-Bromobenzil

2'-Bromo-2-phenylacetophenone, 5.2 g. (0.0189 mole) 2.68 g. (0.0208mole) of selenous acid, 15 ml. of p-dioxane, and 3.6 ml. of water arestirred at reflux for 18 hours. The two-phase supernatant solution iswithdrawn and the residual precipitate of selenium washed with benzene.The combined solution and washings are concentrated to a small volumeunder reduced pressure and the residue is partitioned between benzeneand water. Evaporation of the washed and dried benzene extract underreduced pressure leaves the yellow oily product.

A sample is characterized by conversion to the crystalline derivative,2-phenyl-3-(2-bromophenyl)-quinoxaline. 2-Bromobenzil, 0.58 g. (0.002mole), and o-phenylenediamine, 0.24 g. (0.0022 mole), are heated torefluxing in 10 ml. of absolute ethanol for 3 hours. Evaporation of thesolvent under reduced pressure and crystallization of the residue from95% ethanol gives crystalline product, m.p. 131°-132.5°C. A sample foranalysis melts at 133°-134.5°C. after repeated recrystallizations from95% ethanol. Anal. Calc'd. for C₂₀ H₁₃ BrN₂ : C, 66.51; H, 3.63; N,7.76. Found: C, 66.45; H, 3.55; N, 7.63.

EXAMPLE 3 2-Bromo-α,α,α',α'-tetrafluorobibenzyl

2-Bromobenzil, 2.6 g. (0.009 mole), together with 33 g. of sulfurtetrafluoride, 2 g. of mercury and a trace of hydrogen fluoride, ischarged into a stainless steel autoclave and shaken 30 minutes at roomtemperature, 2 hours at 100°C., 2 hours at 120°C., and 6 hours at 140°C.After cooling and venting the vessel, the mixture is dissolved inbenzene, separated from mercury, and filtered through diatomaceousearth. Evaporation of benzene from the filtrate under reduced pressureleaves the product as a brown solid. Sublimation at 85°-95°C. and 0.1mm. yields white crystals, m.p. 54°-55°C. A sample for analysis isresublimed.

Anal. Calc'd. for C₁₄ H₉ BrF₄ : C, 50.49; H, 2.72; Br, 24.00. Found: C,50.87; H, 2.94; Br, 23.33.

EXAMPLE 4 2-(α,α,β,β-Tetrafluorophenethyl)benzonitrile

A mixture of 3.33 g. (0.01 mole) of2-bromo-α,α,α',α'-tetrafluorobibenzyl, 2.70 g. of cuprous cyanide, 30ml. of dry quinoline, and 3 ml. of dry dimethylformamide are stirred andheated to refluxing for about 30 hours. After cooling and dilution withether, the precipitate is removed by filtration and washed with ether.Solvents are evaporated from the filtrate under reduced pressure leavingthe product as an oily brown solid. Purification is effected by columnchromatography on 150 g. of silica, the product being eluted withbenzene-hexane (3:1). The fractions which show one spot of rf 0.7 on asilica thin layer plate developed with benzene are combined. Evaporationof the solvents under reduced pressure leaves white crystals, m.p.84°-86°C. A sample for analysis is sublimed at 55°C. and 0.05 mm; m.p.85°-86°C.

Anal. Calc'd. for C₁₅ H₉ F₄ N: C, 64.52; H, 3.25; N, 5.02. Found: C,65.50; H, 3.04; N, 4.52.

EXAMPLE 5 2-(α,α,β,β-Tetrafluorophenethyl)benzylamine

Lithium aluminum hydride, 250 mg. (0.0066 mole), is weighed undernitrogen, transferred to a dry, nitrogen-flushed reaction flask, andsuspended in 15 ml. of absolute ether. A solution of 880 mg. (0.0066mole) of aluminum chloride in 15 ml. of absolute ether is addeddropwise. The mixture, containing a white precipitate, is stirred atroom temperature for 5 minutes; then a solution of 0.942 g. (0.00338mole) of 2-(α,α,β,β-tetrafluorophenethyl)benzonitrile in 30 ml. ofabsolute ether is added dropwise. The mixture is stirred at roomtemperature and in a nitrogen atmosphere for about 18 hours. Hydrolysisis effected by the dropwise addition of 4 ml. of water. Afterdecantation of the ethereal layer and washing of the gelatinousprecipitate with two portions of boiling ether, the precipitate issuspended in 20 ml. of 40% aqueous sodium hydroxide and 200 ml. ofwater. The mixture is extracted repeatedly with benzene-ether (1:1).Evaporation of solvents under reduced pressure from the washed and driedorganic extract leaves the product as the residual solid, m.p. 54°-56°C.A sample is purified for analysis by sublimation at 47°C. and 0.05 mm.;m.p. 55°-57°C.

Anal. Calc'd. for C₁₅ H₁₃ F₄ N: C, 63.57; H, 4.62; N, 4.94. Found: C,63.93; H, 4.54; N, 4.94.

The base may be converted to the hydrochloride salt by treating asolution in ethanol with a slight excess of ethanolic hydrogen chloride.Dilution with ether precipitates the hydrochloride, m.p. 244°-247°C.Repeated recrystallizations from ethanol-ether and from isopropylalcohol gives purified material, m.p. 253°-254°C.

Anal. Calc'd. for C₁₅ H₁₃ F₄ N.HCl; C, 56.35; H, 4.41; N, 4.38. Found:C, 56.53; H, 4.15; N, 4.45.

The lactate salt is prepared by treating a solution of2-(α,α,β,β-tetrafluorophenethyl)benzylamine in ethanol with a slightexcess of 85-90% lactic acid. Dilution with ether precipitates thelactate, m.p. 144°-146°C. The melting point is unchanged byrecrystallization from isopropyl alcohol-ether.

Anal. Calc'd. for C₁₅ H₁₃ F₄ N.C.sub. 3 H₆ O₃ : C, 57.90; H, 5.13;Found: C, 58.06; H, 4.88.

EXAMPLE 6 N-Methyl-2-(α,α-β,β-Tetrafluorophenethyl)benzylamine

2-(α,α,β,β-Tetrafluorophenethyl)benzylamine, 1.4 g. (0.005 mole), in 100ml. of ethyl formate, is stirred and heated to refluxing for about 20hours. Evaporation of the solution to dryness and trituration of theresidual solid with petroleum ether givesN-[2-(α,α,β,β-tetrafluorophenethyl)benzyl]formamide, m.p. 61°-75°C.

Lithium aluminum hydride, 290 mg. (0.0077 mole), is weighed undernitrogen, transferred to a dry, nitrogen-flushed reaction flask, andsuspended in 10 ml. of absolute ether. A solution of 1.2 g. (0.00386mole) of N-[2-(α,α,β,β-tetrafluorophenethyl)benzyl]formamide in 25 ml.of absolute ether is added dropwise and the mixture is stirred at refluxfor about 18 hours. After the addition of absolute ether, the mixture iscooled in an ice-bath and hydrolysis is effected by the successivedropwise addition of 0.3 ml. of water, 0.2 ml. of 20% aqueous sodiumhydroxide, and 0.6 ml. of water. The granular precipitate is filteredand washed with ether. Evaporation of the ethereal filtrate underreduced pressure leaves the oily base as the residue. The base isconverted to the hydrochloride salt by treating an ethanolic solutionwith a slight excess of ethanolic hydrogen chloride. The hydrochlorideprecipitates and after recrystallization from absolute ethanol, isobtained as white crystals, m.p. 251°-253°C. a sample for analysis meltsat 252°- 253°C. after recrystallization from absolute ethanol and frommethanolether.

Anal. Calc'd. for C₁₆ H₁₅ N.HCl: C, 57.58; H, 4.83; N, 4.20. Found: C,57.86; H, 4.68; N, 4.41.

EXAMPLE 7 N,N-Dimethyl-2-(α,α,β,β-tetrafluorophenethyl)benzylamine

A solution of 2.2 g. (0.006 mole) of2-(α,α,β,β-tetrafluorophenethyl)benzylamine (±) lactate in 3 ml. of 88%formic acid is treated with 1 g. (0.013 mole) of 37% formaldehyde andthe stirred mixture is heated on the steam bath for about 18 hours.After the addition of 1 ml. of concentrated hydrochloric acid, thesolution is evaporated to dryness under reduced pressure. The residualsyrup is dissolved in 25 ml. of water and the solution is renderedstrongly alkaline with 40% aqueous sodium hydroxide. The base isextracted into benzene. Evaporation of the washed and dried benzeneextract under reduced pressure leaves the product as the residual oil.The base is converted to the hydrochloride salt by treating a solutionin isopropyl alcohol with a slight excess of 8.2 N hydrogen chloride inethanol. The hydrochloride precipitates in white crystals, m.p.190°-192°C. The melting point is unchanged by recrystallization fromisopropyl alcohol.

Anal. Calc'd. for C₁₇ H₁₇ F₄ N.HCl: C, 58.71; H, 5.22; N, 4.03; Cl,10.19. Found: C, 59.12; H, 5.22; N, 3.83; Cl, 10.10.

EXAMPLES 8-66N,N-Dialkyl-2-[2-(phenyl-1,1,2,2-tetrafluoro)ethyl]-benzylamine

Using the appropriate starting materials, the following products arealso prepared as set forth in the preceding description.

    __________________________________________________________________________         Flow Sheet                                                               Example                                                                            Formula                                                                              A   n X     X'                                                    __________________________________________________________________________     8   I      phenyl                                                                            2 H     chloro                                                 9   "      "   " H     fluoro                                                10   "      "   " H     methyl                                                11   "      "   " H     tert. butyl                                           12   "      "   " H     methoxy                                               13   "      "   " H     ethoxy                                                14   "      "   " H     trifluoromethyl                                       15   "      "   " H     methylsulfonyl                                        16   "      "   " H     methylmercapto                                        17   "      "   " H     dimethylsulfamoyl                                     18   "      "   " methyl                                                                              methyl                                                19   "      "   " chloro                                                                              methyl                                                20   "      "   " chloro                                                                              dimethylsulfamoyl                                     21   "      "   " chloro                                                                              chloro                                                22   II     "   " H     chloro                                                23   "      "   " H     fluoro                                                24   "      "   " H     methyl                                                25   "      "   " H     tert. butyl                                           26   "      "   " H     methoxy                                               27   "      "   " H     ethoxy                                                28   "      "   " H     trifluoromethyl                                       29   "      "   " H     methylsulfonyl                                        30   "      "   " H     methylmercapto                                        31   "      "   " H     dimethylsulfamoyl                                     32   "      "   " methyl                                                                              methyl                                                33   "      "   " chloro                                                                              methyl                                                34   "      "   " chloro                                                                              dimethylsulfamoyl                                     35   "      "   " chloro                                                                              chloro                                                36   III    "   " H     chloro                                                37   "      "   " H     fluoro                                                38   III    phenyl                                                                            2 H     methyl                                                39   "      "   " H     tert. butyl                                           40   "      "   " H     methoxy                                               41   "      "   " H     ethoxy                                                42   "      "   " H     trifluoromethyl                                       43   "      "   " H     methylsulfonyl                                        44   "      "   " H     methylmercapto                                        45   "      "   " H     dimethylsulfamoyl                                     46   "      "   " methyl                                                                              methyl                                                47   "      "   " chloro                                                                              methyl                                                48   "      "   " chloro                                                                              dimethylsulfamoyl                                     49   "      "   " chloro                                                                              chloro                                                50   IV     "   " H     chloro                                                51   "      "   " H     fluoro                                                52   "      "   " H     methyl                                                53   "      "   " H     tert. butyl                                           54   "      "   " H     methoxy                                               55   "      "   " H     ethoxy                                                56   "      "   " H     trifluoromethyl                                       57   "      "   " H     methylsulfonyl                                        58   "      "   " H     methylmercapto                                        59   "      "   " H     dimethylsulfamoyl                                     60   "      "   " methyl                                                                              methyl                                                61   "      "   " chloro                                                                              methyl                                                62   "      "   " chloro                                                                              dimethylsulfamoyl                                     63   "      "   " chloro                                                                              chloro                                                64   VI     "   " Derivatives of each of the                                                    compounds of Formula IV above                                                 in which R.sub.2 and R.sub.3 are methyl,                                      ethyl, propyl, butyl or amyl.                               65   VII    phenyl                                                                            2 Derivatives of compounds                                                      of Formula IV above in                                                        which Alk is methyl, ethyl,                                                   propyl, butyl or amyl.                                      66   IIE    "   " Derivatives of the compounds                                                  of Formula IV above in                                                         ##STR2##                                                                     1-pyrrolidinyl, 4-morpho-                                                     linyl, 4-thiomorpholinyl                                                      or 1-lower-alkyl-4-                                                           piperazinyl, and in which                                                     Alk is methyl, ethyl,                                                         propyl, butyl or amyl.                                      __________________________________________________________________________

EXAMPLE 67N,N-Dialkyl-2-[2-(heterocyclic-1,1,2,2-tetrafluoro)ethyl]-benzylamine

When the procedures of Examples 8-66 are repeated using appropriateamounts of the corresponding starting materials except that the Asubstituent is either pyridine, pyrimidine, thiazole, thiophene,imidazole or oxazole, the corresponding products are obtained.

EXAMPLE 68 2-(α,α,β,β-Tetrafluorophenethyl)benzoic acid

In a dry apparatus maintained under a nitrogen atmosphere, 40 mg.(0.00165 g. atom) of magnesium turnings are suspended in 0.5 ml. oftetrahydrofuran containing a crystal of iodine. A solution of 0.5 g(0.0015 mole) of 2-bromo-α,α,α',α'-tetrafluorobibenzyl in 1.5 ml. oftetrahydrofuran and a solution of 0.3 g. of ethylene bromide in 4 dropsof tetrahydrofuran are added dropwise alternately until the reaction isinitiated. The mixture then is heated to refluxing and the remainingsolution of the 2-bromo-α,α,α',α'-tetrafluorobibenzyl is added.Refluxing is continued until all of the magnesium is consumed. Themixture is cooled in ice and diluted with 3 ml. of tetrahydrofuran.Carbon dioxide is passed over the surface of the stirred mixture for 1hour and then passed through the solution for 3 minutes. After another 1hour in the cold, the mixture is allowed to stand at room temperaturefor about 16 hours.

The bulk of the solvent is evaporated under reduced pressure and below40°C. and the residue is dissolved in benzene. After treatment of theice-cold solution with water and dilute hydrochloric acid, the organicphase is separated, washed with water, and evaporated to dryness underreduced pressure. The residual oil is triturated with 1 N sodiumhydroxide and the mixture is centrifuged. The clear supernatant alkalinesolution is decanted, acidified with 6 N hydrochloric acid, and thesolid product extracted into benzene. Evaporation of the washed benzeneextract and recrystallization of the residual solid from hexane giveswhite crystals, m.p. 130°-132°C. An analytical sample melts at131°-132°C. after recrystallization from cyclohexane and sublimation at100° and 0.2 mm.

Anal. Calc'd. for C₁₅ H₁₀ F₄ O₂ : C, 60.36; H, 3.38. Found: C, 60.45; H,3.48.

EXAMPLE 69 2(α,α,β,β,γ,γ-hexafluorophenylpropyl)benzylamine

A. Into a round bottom flask equipped with a paddle stirrer is placed19.3 g. (0.482 mole) of sodium hydroxide, 134.5 g. of water, 68.8 g. of95% ethanol, and 45.4 g. (0.38 mole) of acetophenone. The solution isstirred vigorously and is cooled in an ice bath such that thetemperature is kept between 15°C. and 30°C. 2-Bromo-benzaldehyde (69.89g., 0.378 mole) is added all at once and the mixture is stirredvigorously for several hours. After standing at room temperatureovernight, the mixture is diluted with 300 ml. of ether. The ether phaseis separated and is washed with water until the washings are neutral tolitmus paper. The ether solution is dried (MgSO₄), and removal of theether gives 103.8 g. of 2-bromobenzalacetophenone as a yellow oil.

B. 2-Bromobenzalacetophenone (103.8 g., 0.37 mole) is dissolved in 226ml. of carbon tetrachloride. The solution is stirred and cooled in anice bath. Bromine (60.50 g., 0.38 mole) is added dropwise over a periodof 0.5 hour, and after this addition is complete, the mixture is stirredanother 0.5 hour. The crystalline product is removed by filtration, andis washed with hot absolute ethanol, and dried to give 87.7 g. of2-bromobenzalacetophenone dibromide.

C. 2-Bromobenzalacetophenone dibromide (87.7 g. 0.196 mole) is placed ina round bottom flask equipped with stirrer, dropping funnel, and refluxcondenser with calcium chloride drying tube. Dry methanol (100 ml.) isadded and the mixture is stirred. A solution of 9.01 g. (0.392 mole) ofsodium in 95 ml. of absolute methanol is added rapidly and the mixtureis heated under reflux for one hour. The cooled mixture is made neutralby addition of approximately 0.5 ml. concentrated hydrochloric acid andis diluted with 65 ml. of water. On stirring the mixture,crystallization occurs. The product is removed by filtration, washedwith water, absolute methanol, and finally is recrystallized frommethanol to give 35.90 g. of3-(2-bromophenyl)-3-methoxy-1-phenylpropen-1-one.

D. A mixture of 19.34 g. of3-(2-bromophenyl)-3-methoxy-1-phenylpropen-1-one, 200 ml. of absolutemethanol and 20 ml. of 6 N hydrochloric acid is stirred and refluxed for1.5 hours. The bulk of methanol is evaporated off on a rotary evaporatorat 60°C. The residue is diluted with water (500 ml.) and is extractedwith two 200 ml. portions of benzene. These benzene extracts arecombined, washed with water, saturated sodium bicarbonate solution,water, and dried over magnesium sulfate. Filtration and evaporation ofthe benzene gives 19.19 g. of (2-bromobenzoyl)-benzoylmethane.

E. Into a round bottom flask equipped with a dropping funnel,thermometer, stirrer, gas inlet tube and gas outlet tube is placed 15.35g. (0.0615 mole) of (2-bromobenzoyl)-benzoylmethane and 5 ml. ofchloroform. The solution is cooled in an ice bath from 0°C. to 15°C. anda solution of bromine (21.7 g., 0.135 mole) in 55 ml. of chloroform isadded dropwise over 30 minutes. During this addition, a stream of air ispassed over the surface of the solution to blow out the by-product ofhydrogen bromide. After the addition is completed, the solution isstirred for an additional 15 minutes, and then the chloroform is removedon a rotary evaporator at a temperature of 25°C. to 40°C.

To the oily residue is added a hot solution of 11.2 g. (0.136 mole) offreshly fused sodium acetate dissolved in 55 ml. of glacial acetic acid.The solution is stirred magnetically and is heated under reflux for 2hours. The bulk of the acetic acid is removed by evaporation on therotary evaporator. The residue is dissolved in ether and this etherphase is washed with water (5 × 250 ml.) and dried over magnesiumsulfate. Evaporation of the ether gives a bright orange, viscous syrupthat is distilled at 170°-195°C. (0.5 mm). This distillate isredistilled to give 1-(2-bromophenyl)-3-phenylpropan-1,2,3-trione, b.p.174°-177°C. (0.3 mm), 8.31 gm.

Anal. Calc'd. for C₁₅ H₉ BrO₃ : C, 56.81; H, 2.86. Found: C, 56.63; H,3.02.

F. A mixture of 8.31 g. (0.0262 mole) of1-(2-bromophenyl)-3-phenylpropan-1,2,3-trione, 112 g. of sulfurtetrafluoride, 1 g. of mercury and 10 ml. of hydrogen fluoride is heatedin a stainless steel bomb at 100°C. for 2 hours, 120°C. for 2 hours, and140°C. for 6 hours. The cooled contents of the bomb are dissolved inhexane and filtered. Evaporation of the hexane from the filtrate gives alight tan oil. Fractional distillation of the oil gives2-(α,α,β,β,γ,γ-hexafluorophenylpropyl)-bromobenzene, b.p. 83°-87°C.(0.05 mm.), 4.64 g.

Anal. Calc'd. for C₁₅ H₉ BrF₆ : C, 47.02; H, 2.37; F, 29.75. Found: C,46.94; H, 2.67; F, 29.52.

G. A mixture of 4.64 g. (0.0121 mole) of2-(α,α,β,β,γ,γ-hexafluorophenylpropyl)-bromobenzene, 1.19 g. (0.0133mole) of cuprous cyanide, 46 ml. of quinoline, and 4.6 ml. ofdimethylformamide is stirred magnetically and heated under reflux for 24hours. The dark reaction mixture is diluted with ether and 6 Nhydrochloric acid, and the entire mixture is filtered through a pad ofdiatomaceous earth. The ether phase is withdrawn and is washed with 3 Nhydrochloric acid, water, and dried over magnesium sulfate. Evaporationof the ether gives 4.06 g. of oil that distills at 137°-140°C. (1.0mm.). This distillate crystallizes immediately and is recrystallizedfrom hexane to give 2.37 g. of sparkling white plates, m.p. 72°-73°C.

H. To a solution of 0.46 g. (0.012 mole) of lithium aluminum hydride in20 ml. of dry ether is added dropwise over 15 minutes a solution of 1.6g. (0.012 mole) of aluminum chloride dissolved in 25 ml. of ether. Thesolution is stirred for approximately 15 minutes, then a solution of2.00 g. (0.00608 mole) of2-(α,α,β,β,γ,γ-hexafluorophenylpropyl)benzonitrile dissolved in 25 ml.of dry ether is added dropwise over 15 to 20 minutes. The mixture isstirred overnight at room temperature.

The excess lithium aluminum hydride is decomposed by dropwise additionof 5 N sodium hydroxide until a clear ether phase is obtained. The etheris decanted and the gelatinous residue that remains is thoroughlyextracted with ether (3 × 100 ml.). The ether phases are combined anddried (MgSO₄). Evaporation of the ether gives 1.98 g. of a clear,colorless oil. This oil is dissolved in ether and is treated with dry,gaseous hydrogen chloride. The white, crystalline precipitate is removedby filtration and is recrystallized from ethyl acetate to give2-(α,α,β,β-γ,γ-hexafluorophenylpropyl)benzylamine hydrochloride, m.p.162°-163.5°C.

Anal. Calc'd. for C₁₆ H₁₃ F₆ N.HCl: C, 52.12; H, 3.55; Cl, 9.61; F,30.92. Found: C, 52.42; H, 3.77; Cl, 9.53; F, 30.70.

EXAMPLE 70 4-Fluoro-2-(α,α,β,β-tetrafluorophenethyl)benzylamine

A. 2-Bromo-4-fluorobenzonitrile

A solution of 10.9 g. (0.05 mole) of 2-bromo-4-fluorobenzamide in 50 ml.of dry pyridine is stirred and cooled in an ice-bath while 11.2 g.(0.0525 mole) of trifluoroacetic anhydride is added dropwise. After 2hours at room temperature, the bulk of the solvent is evaporated underreduced pressure and the residue is dissolved in ether. Evaporation ofthe washed and dried ethereal extract under reduced pressure leaves theproduct as the residual solid. Sublimation at 55°C. and 0.05 mm. yieldswhite crystals, m.p. 75°-76.5°C. A sample from a previous experiment wasresublimed for analysis, m.p. 77°-78°C.

Anal. Calc'd. for C₇ H₃ BrFN: C, 42.00; H, 1.50; N, 7.00. Found: C,41.41; H, 1.68; N, 6.92.

B. 2'-Bromo-4'-fluoro-2-phenylacetophenone

A solution of 2-bromo-4-fluorobenzonitrile, 6.0 g. (0.03 mole) in 35 ml.of absolute ether is added dropwise to a stirred solution ofbenzylmagnesium chloride prepared from 2.9 g. (0.12 g. atom) ofmagnesium turnings and 15.2 g. (0.12 mole) of benzyl chloride in 65 ml.of absolute ether in a nitrogen atmosphere. The mixture is stirred atroom temperature for about 18 hours. After cooling in an ice-bath, theadduct is hydrolyzed by the dropwise addition of 100 ml. of 0.5 M.citric acid. The organic phase is separated and the aqueous phasereextracted with several portions of benzene. The combined organiclayers are extracted with 45 ml. of ice-cold 6 N hydrochloric acid innseveral portions and the combined acid extracts are heated on the steambath for 45 minutes. The product separates as an oil and is extractedinto benzene. Evaporation of the washed and dried benzene extract leavesthe yellow oily product that is purified by distillation; b.p.112°-115°C./ 0.05 mm.

C. 2-Bromo-4-fluorobenzil

By following essentially the same procedures described in Example 2,2'-bromo-4'-fluoro-2-phenyl-acetophenone is oxidized to2-bromo-4-fluorobenzil. The yellow crystalline product, m.p. 62°-66°C.,is recrystallized from 95% ethanol to obtain material of m.p.67°-68.5°C. A sample for analysis melts at 67.5°-69°C. after sublimationat 60° and 0.1 mm.

Anal. Calc'd for C₁₄ H₈ BrFO₂ : C, 54.72; H, 2.61; Br, 26.06. Found: C,55.08; H, 2.84; Br, 25.75.

D. 2-Bromo-4,α,α,α',α'-pentafluorobibenzyl

By following essentially the same procedures described in Example 3,2-bromo-4-fluorobenzil is converted to2-bromo-4,α,α,α',α'-pentafluorobibenzyl. Sublimation of the crude brownsolid at 50°C. and 0.1 mm. yields white crystals, m.p. 47°-48°C. Asample for analysis is resublimed.

Anal. Calc'd. for C₁₄ H₈ BrF₅ : C, 47.89; H, 2.30; Br, 22.76. Found: C,48.44; H, 2.53; Br, 22.47.

E. 4-Fluoro-2-(α,α,β,β-tetrafluorophenethyl)benzonitril

A mixture of 4.9 g. (0.0139 mole) of2-bromo-4,α,α,α',α'-pentafluorobibenzyl, 3.70 g. of cuprous cyanide, 60ml. of dry quinoline and 6 ml. of dry dimethylformamide is stirred andheated to refluxing for 18 hours. After cooling in ice, the precipitateis removed by filtration and washed with a mixture of benzene and ether.Solvents are evaporated from the filtrate under reduced pressure leavingthe crude product as an oily black solid. Purification is effected bycolumn chromatography on 300 g. of silica, the product being eluted withbenzene-carbon tetrachloride (2:1). The fractions containing a majorcomponent of rf 0.65 on a fluorescent silica thin layer plate developedwith benzene are combined. Evaporation of the solvents under reducedpressure leaves a solid that is sublimed at 60°C. and 0.1 mm; m.p.68°-70°C. A sample for analysis is resublimed.

Anal. Calc'd. for C₁₅ H₈ F₅ N: C, 60.62; H, 2.71; N, 4.71. Found: C,61.33; H, 2.76; N, 4.70.

F. 4-Fluoro-2-(α,α,β,β-tetrafluorophenethyl)benzylamine

By following essentially the same procedures described in Example 5,4-fluoro-2-(α,α,β,β-tetrafluorophenethyl)benzonitrile is reduced to4-fluoro-2-(α,α,β,β-tetrafluorophenethyl)benzylamine. Sublimation of thecrude product at 70°C. and 0.05 mm. gives white crystals, m.p.52.5°-54°C. A sample for analysis is resublimed; m.p. 53°-54.5°C.

Anal. Calc'd. for C₁₅ H₁₂ F₅ N: C, 59.80; H, 4.02; N, 4.65. Found: C,60.11; H, 4.07; N, 4.61.

EXAMPLE 71 2-(4,α,α,β,β-Pentafluorophenethyl)benzylamine

A. 2'-Bromo-2-(p-fluorophenyl)-acetophenone

By following essentially the same procedures described in Example 1,2'-bromo-2-(p-fluorophenyl)-acetophenone is obtained from2-bromobenzonitrile and p-fluorobenzylmagnesium chloride. Distillationof the yellow crystalline product yields almost colorless crystals, b.p.130°-132°C./0.1 mm.; m.p. 44°-46°C.

Anal. Calc'd. for C₁₄ H₁₀ BrFO: C, 57.37; H, 3.44; Br, 27.27. Found: C,58.04; H, 3.59; Br, 26.83.

B. 2-Bromo-4'-fluorobenzil

By following essentially the same procedures described in Example 2,2'-bromo-2-(p-fluorophenyl)-acetophenone is oxidized to2-bromo-4'-fluorobenzil. The yellow crystalline product, m.p. 72°-78°C.,is recrystallized from 95% ethanol to obtain material of m.p. 76.5°-78.5°C. Repeated recrystallization from 95% ethanol yields a sample foranalysis, m.p. 79°-80°C.

Anal. Calc'd. for C₁₄ H₈ BrFO₂ : C, 54.72; H, 2.61; Br, 26.06. Found: C,55.07; H, 2.67; Br, 25.93.

C. 2-Bromo-4',α,α,α',α'-pentafluorobibenzyl

By following essentially the same procedures described in Example 3,2-bromo-4'-fluorobenzil is converted to2-bromo-4',α,α,α',α'-pentafluorobibenzyl. Sublimation of the crude brownsolid at 60°-70°C. and 0.1 mm. yields white crystals, m.p. 52°-53.5°C.

Anal. Calc'd. for C₁₄ H₈ BrF₅ : C, 47.89; H, 2.30; Br, 22.76. Found: C,48.21; H, 2.37; Br, 23.04.

D. 2-(4,α,α,β,β-pentafluorophenethyl)benzonitrile

A mixture of 8.5 g. (0.024 mole) of2-bromo-4,α,α,α',α'-pentafluorobibenzyl, 6.4 g. of cuprous cyanide, 75ml. of dry quinoline and 7.5 ml. of dry dimethylformamide is stirred andheated to refluxing for 34 hours. The precipitate is removed from thecooled mixture by filtration and washed with a mixture of benzene andether. Solvents are evaporated from the filtrate under reduced pressureleaving the product as an oily black solid. Sublimation at 80°C. and0.05 mm. yields light brown solid, m.p. 90°-93°C. Purification iseffected by column chromatography on 300 g. of silica, the product beingeluted with benzene-hexane (1:1). The fractions that show one spot of rf0.85 on a fluorescent silica thin layer plate developed with benzene arecombined. Evaporation of the solvent under reduced pressure leaves whitecrystals, m.p. 96.5°-97.5°C. A sample for analysis is sublimed.

Anal. Calc'd. for C₁₅ H₈ F₅ N: C, 60.62; H, 2.71; N, 4.71. Found: C,60.81; H, 2.57; N, 4.57.

E. 2-(4,α,α,β,β-Pentafluorophenethyl)benzylamine

By following essentially the same procedures described in Example 5,2-(4,α,α,β,β-pentafluorophenethyl)benzonitrile is reduced to2-(4,α,α,β,β-pentafluorophenethyl)benzylamine. The crude product, m.p.64°-66°C., is sublimed at 60°C. and 0.05 mm. yielding white crystals,m.p. 64°-65.5°C.

Anal. Calc'd. for C₁₅ H₁₂ F₅ N: C, 59.80; H, 4.02; N, 4.65. Found: C,59.80; H, 3.93; N, 4.67.

EXAMPLE 72 2-[2-(α,α,β,β -Tetrafluorophenethyl)phenyl]-imidazoline

2-(α,α,β,β -Tetrafluorophenethyl)benzonitrile, 2.06 g. (0.0074 mole),together with 1.2 g. (0.02 mole) of ethylenediamine and 3 drops ofcarbon disulfide, is heated in a sealed tube at 160°-165°C. for 18hours. After cooling in an ice-bath, the tube is opened and the contentsare poured into water. The orange gum that separates is washed withwater by decantation and then dissolved in ethyl acetate. The ethylacetate solution is extracted with 3N hydrochloric acid. The combined,ice-cold, acid extracts are rendered strongly alkaline with 40% aqueoussodium hydroxide and the oily base is extracted into ethyl acetate. Thewashed and dried ethyl acetate extract is concentrated under reducedpressure to a volume of about 25 ml. and 0.6 ml. of 8N ethanolichydrogen chloride is added. Dilution with an equal volume of absoluteether precipitates the white crystalline hydrochloride salt of theproduct, m.p. 263°-266°C., sintering at 258°C. Recrystallization fromacetone gives a purified sample, m.p. 266°-267°C.

Anal. Calc'd. for C₁₇ H₁₄ F₄ N₂ .HCl: C, 56.90; H, 4.21; N, 7.81. Found:C, 56.94; H, 4.03; N, 7.60.

EXAMPLE 73 2-(α,α,β,β-Tetrafluorophenethyl)phenethylamine

A. 2-(α,α,β,β-Tetrafluorophenethyl)benzyl alcohol

Lithium aluminum hydride, 530 mg. (0.0139 mole), is weighed undernitrogen, transferred to a dry-nitrogen-flushed reaction flask, andsuspended in 15 ml. of absolute ether. A solution of 4.15 g. (0.0139mole) of 2-(α,α,β,β-tetrafluorophenethyl)benzoic acid in 35 ml. ofabsolute ether is added dropwise. The mixture is stirred at roomtemperature for 30 minutes and allowed to stand overnight in a nitrogenatmosphere. Hydrolysis is effected by the dropwise addition of 1 ml. ofwater. The precipitate is removed by filtration, and washed with ether.Evaporation of the dried ethereal filtrate under reduced pressure leavesthe product as a white solid, m.p. 80°-81°C. A sample for analysis issublimed at 70°C. and 0.1 mm.

Anal. Calc'd. for C₁₅ H₁₂ F₄ O: C, 63.37; H, 4.26; F, 26.74. Found: C,63.78; H, 4.27; F, 26.38.

B. 2-(α,α,β,β-Tetrafluorophenethyl)benzyl bromide

A suspension of 3.3 g. (0.0116 mole) of2-(α,α,β,β-tetrafluorophenethyl)benzyl alcohol in 15 ml. of 48%hydrobromic acid is stirred and heated on the steam bath for 3 hours.The product crystallizes from the cooled mixture and is collected anddissolved in benzene. Evaporation of the washed and dried benzeneextract under reduced pressure and sublimation of the residual solid at60°C. and 0.05 mm. yields white crystals, m.p. 70°-77°C. A sample foranalysis from a previous preparation was purified by columnchromatography on silica, eluting the product with benzene-carbontetrachloride (2:1). The fractions that showed one spot of rf 0.85 on afluorescent silica, thin layer plate developed with benzene werecombined and the solvent evaporated under reduced pressure. The residualsolid, m.p. 78°-82°C., was sublimed at 60°C. and 0.05 mm. to yieldproduct, m.p. 80.5°-82°C.

Anal. Calc'd. for C₁₅ H₁₁ BrF₄ : C, 51.89; H, 3.20; Br, 23.02. Found: C,52.18; H, 3.32; Br, 22.89.

C. 2-(α,α ,β ,β-Tetrafluorophenethyl)phenylacetonitrile

2-(α,α,β ,β-Tetrafluorophenethyl)benzyl bromide, 3.5 g. (0.01 mole), and2.0 g. (0.0308 mole) of potassium cyanide are dissolved in 35 ml. ofacetone - 5 ml. of water and the solution is heated to refluxing forabout 18 hours. The organic phase is separated, acetone is distilledunder reduced pressure, and the residual oil is dissolved in benzene.Evaporation of the washed and dried benzene extract under reducedpressure leaves the product as the residual brown oil.

D. 2-(α,α,β,β -Tetrafluorophenethyl)phenethylamine

By following essentially the same procedures described in Example 5,2-(α,α,β,β -tetrafluorophenethyl)phenylacetonitrile is reduced to 2-(α,α,β ,β-tetrafluorophenethyl)phenethylamine. The product, a yellow oil, isconverted to the hydrochloride salt by treating an ethanolic solutionwith a slight excess of 8.2N hydrogen chloride in ethanol. Dilution withabsolute ether precipitates the product as white crystals, m.p.212°-214°C. Recrystallization from absolute ethanol-absolute etheryields a purified sample, m.p. 213.5°-215.5°C.

Anal. Calc'd. for C₁₆ H₁₅ F₄ N.HCl: C, 57.58; H, 4.83; N, 4.20. Found:C, 57.88; H, 4.78; N, 4.25.

EXAMPLE 74 N-Benzyl-2-(α,α,β,β -tetrafluorophenethyl)benzylamine

A mixture of 3.9 g. (0.0138 mole) of 2-(α,α,β,β-tetrafluorophenethyl)benzylamine, 1.77 g. (0.014 mole) of benzylchloride, 2.5 g. of anhydrous potassium carbonate, and 25 ml. of benzeneis stirred and heated to refluxing for about 40 hours. After filtration,the solvent is evaporated under reduced pressure, leaving the product asthe residual oil. Purification is effected by column chromatography on250 g. of silica, the product being eluted with 1% methanol inchloroform. The fractions that show one spot of rf 0.7 on a fluorescentsilica thin layer plate developed with 5% methanol in chloroform arecombined. Evaporation of the solvent under reduced pressure leaves theproduct as the residual oil. The base is converted to the hydrochloridesalt by treating an ethanolic solution with a slight excess of 8Nhydrogen chloride in ethanol. Dilution with absolute ether precipitatesthe hydrochloride as white crystals, m.p. 188°-189.5°C.Recrystallization from acetone yields a purified sample, m.p.188.5°-190°C.

Anal. Calc'd. for C₂₂ H₁₉ F₄ N.HCl: C, 64.48; H, 4.92; Cl, 8.65. Found:C, 64.75; H, 4.89; Cl, 8.64.

EXAMPLE 75 α-Methyl-2-(α,α,β,β-tetrafluorophenethyl)benzylamine

A. Methyl 2-(α,α,β,β-tetrafluorophenethyl)phenyl ketimine

A solution of 19.3 g. (0.0685 mole) of2-(α,α,β,β-tetrafluorophenethyl)benzonitrile in 150 ml. of absoluteether is added dropwise to a stirred solution of methylmagnesium bromideprepared from 4.8 g. (0.2 g. atom) of magnesium turnings and about 25 g.(0.26 mole) of methyl bromide in 150 ml. of absolute ether in a nitrogenatmosphere. The mixture is stirred at reflux for about 16 hours. Aftercooling in an ice-bath, the adduct is hydrolyzed by the dropwiseaddition of 20 ml. of water. The organic phase is decanted and thegelatinous precipitate is washed thoroughly with ether. The combinedethereal extracts are extracted with 45 ml. of ice-cold 6N hydrochloricacid in several portions. After further chilling of the combined acidextracts, the precipitate of the hydrochloride salt of the product iscollected and washed with ether. After prolonged drying in vacuo, thecrystalline hydrochloride melts at 144°-146°C., with previous sintering.Repeated recrystallizations from isopropyl alcohol - absolute etherafford an analytical sample, m.p. 147°-148.5°C.

Anal. Calc'd. for C₁₆ H₁₃ F₄ N.HCl: C, 57.94; H, 4.25; N, 4.22. Found:C, 58.08; H, 4.18; N, 4.39.

B. α-Methyl-2-(α,α,β,β-tetrafluorophenethyl)benzylamine

Lithium aluminum hydride, 1.05 g. (0.0276 mole), is weighed undernitrogen, transferred to a dry, nitrogen-flushed reaction flask, andsuspended in 25 ml. of dry, peroxide-free, tetrahydrofuran. The mixtureis stirred and cooled in an ice-bath while a solution of 4.3 g. (0.013mole) of methyl 2-(α,α,β,β-tetrafluorophenethyl)phenyl ketiminehydrochloride in 70 ml. of tetrahydrofuran is added dropwise. Themixture is stirred at room temperature and in a nitrogen atmosphere forabout 18 hours. After cooling in an ice-bath, hydrolysis is effected bythe successive dropwise addition of 1 ml. of water, 1 ml. of 20% aqueoussodium hydroxide, and 3 ml. of water. The precipitate is removed byfiltration and washed with ether. Evaporation of the dried etherealfiltrate under reduced pressure leaves the product as the red oilyresidue.

The base may be converted to the hydrogen maleate salt by heating asolution in isopropyl alcohol with a slight excess of a solution ofmaleic acid in isopropyl alcohol. Dilution with absolute etherprecipitates the hydrogen maleate as white crystals, m.p. 153°-154°C.dec. Repeated recrystallizations from isopropyl alcohol-ether affordpurified material, m.p. 157°-158°C. dec.

Anal. Calc'd. for C₁₆ H₁₅ F₄ N.C.sub. 4 H₄ O₄ : C, 58.11; H, 4.63;Found: C, 58.11; H, 4.64.

EXAMPLE 76 Prevention or Modification of Ventricular Arrhythmia

Beagle dogs of either sex and weighing from 6 to 10 kg. are anesthetizedby the administration of vinbarbital employing a dose of 50 mg./kg. ofbody weight and the mean arterial pressure and the electrocardiogram(Lead II) are recorded. The animals are artificially respired and thethorax opened at the fourth or fifth interspace. The pericardium isopened and a portion of the anterior descending coronary artery justdistal to the origin is freed from the surrounding tissue. Mecamylamineis administered to slow the heart rate and 10 minutes later the compoundto be tested for antiarrhythmic effect is administered intravenously.Ten minutes after administration of the test compound, 0.0035 ml./kg. oftetrafluorohexachlorobutane (TFHCB), a sclerosing agent which producesmyocardial infarction and arrhythmia in dogs (Ascanio et al., J. Am.Physiol. 209: 1081-1088(1965)) is injected into the coronary artery. Incontrol animals, this dose of TFHCB produces a ventricular arrhythmia in100% of the animals tested and death in 33% of the animals tested as aresult of ventricular fibrillation.

Following injection of the sclerosing agent, an electrocardiogram isrecorded at two-minute intervals for one hour and the average number ofelectrical (ECG) complexes per minute and the per cent normal complexescalculated. The data obtained with different doses of the test compoundsis plotted and the dose estimated to protect the animals is estimatedgraphically (ED₈₀ mg./kg.). This figure indicates that 80% of all theelectrical (ECG) complexes are normal.

The compound 2-(α,α,β,β-tetrafluorophenethyl)benzylamine is tested atdoses of from 0.02 to 2.5 mg./kg. The average per cent of normalcomplexes calculated is from 20 to 97. Thus, the estimated ED₈₀ is equalto 0.16 mg./kg. compared with quinidine sulfate which, when tested undersimilar conditions at doses of 2.5, 5.0 and 10.0 mg./kg. gave averageper cent of normal values of 25, 51 and 90, respectively, giving anestimated ED₈₀ = 8.8 mg./kg.

EXAMPLE 77 Capsules

Capsules for oral administration are prepared by dispersing the activeingredient in lactose and magnesium stearate and encapsulating themixture in standard soft gelatin capsules so that each capsule will havethe following composition.

    ______________________________________                                                               Per Capsule                                            ______________________________________                                        2-(α,α,β,β-tetrafluorophenethyl)-                       benzylamine hydrochloride                                                                          5         mg.                                            Lactose              430       mg.                                            Magnesium Stearate   5         mg.                                            ______________________________________                                    

EXAMPLE 78 Parenteral Solution

A solution suitable for administration for injection is prepared bymixing the active ingredient, dextrose, methylparaben, propylparaben anddistilled water, so that each one will have the following composition,and sterilized.

    ______________________________________                                                              Per ml.                                                 ______________________________________                                        2-(α,α,β,β-tetrafluorophenethyl)-                       benzylamine hydrochloride                                                                          5         mg.                                            Dextrose             44        mg.                                            Methylparaben        1.5       mg.                                            Propylparaben        0.2       mg.                                            Water for Injection  q.s.                                                     ______________________________________                                    

EXAMPLE 79 Tablets

Tablets for oral administration are prepared by mixing the activeingredient with appropriate amounts of excipients and binding agents,formed into tablets by a conventional tableting machine, and coated sothat each tablet will have the following composition.

    ______________________________________                                                             Per Tablet                                               ______________________________________                                        2-(α,α,β,β-tetrafluorophenethyl)-                       benzylamine hydrochloride                                                                          10        mg.                                            Cellulose filter aid 11        mg.                                            Lactose              9         mg.                                            Calcium Phosphate Dibasic                                                                          143       mg.                                            Guar Gum             6.1       mg.                                            Corn Starch          4         mg.                                            Magnesium Stearate   0.9       mg.                                            Opaque Yellow Film Coating                                                                         3         mg.                                            ______________________________________                                    

The preceding three examples, Examples 77, 78 and 79, are repeated, andcompositions for the treatment or prevention of arrhythmia are preparedby substituting any of the compounds specifically illustrated above inplace of the tetrafluorophenethylbenzylamine as one of the activecompounds useful in our invention.

EXAMPLE 80 α,N-Dimethyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine

α-Methyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine, 1.06 g. (0.00357mole), in 50 ml. of ethylformate is stirred and heated to refluxing forabout 21 hours. Evaporation of the solution to dryness and triturationof the residue with hexane givesN-[α-methyl-2-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide, m.p.94.5°-99°C. Recrystallizations from ether-petroleum ether and isopropylalcohol-water afford a purified sample, m.p. 103°-105°C.

By following essentially the same procedures described in Example 6,N-[α-methyl-2-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide isreduced to α,N-dimethyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine.The product, a yellow oil, is converted to the hydrogen fumarate salt bytreating an ethereal solution with a solution of a slight excess offumaric acid in absolute ethanol. The hydrogen fumarate precipitates andafter recrystallization from acetone, is obtained as white crystals,m.p. 175°-176°C. The melting point is unchanged by furtherrecrystallization from acetone.

Anal. calc'd for C₁₇ H₁₇ F₄ N.C.sub. 4 H₄ O₄ : C,59.01; H,4.95; N,3.28.Found: C,58.84; H,5.09; N,3.28.

The hydrochloride salt is prepared by treating a solution of the base inabsolute ethanol with a slight excess of ethanolic hydrogen chloride.Dilution with absolute ether precipitates the hydrochloride that isrecrystallized from acetone-absolute ether to obtain the analyticalsample, m.p. 190°-192°C.

Anal. calc'd for C₁₇ H₁₇ F₄ N.HCl: C,58.71; H,5.22; N,4.05. Found:C,58.47; H,5.40; N,4.08.

EXAMPLE 81 (+) α,N-Dimethyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine

Racemic α,N-dimethyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine, 9.5g. (0.0305 mole), in 25 ml. of boiling absolute ethanol is treated witha solution of 2.3 g. (0.0153 mole) of (-) tartaric acid in 20 ml. ofabsolute ethanol. Crystallization is initiated by seeding and thesolution is allowed to stand at room temperature until no furtherprecipitation occurs. After collection of the (-) tartrate, theethanolic mother liquor is evaporated to dryness under reduced pressureand the residual solid suspended in water. The mixture is renderedalkaline with saturated sodium carbonate solution and the oily base isextracted into hexane. Evaporation of the washed and dried hexaneextract under reduced pressure leaves the (+) base weighing 1.35 g.

The (+) base is dissolved in 4 ml. of absolute ethanol and treated witha solution of 326 mg. (0.00217 mole) of (+) tartaric acid in 3 ml. ofabsolute ethanol. The (+) tartrate separates in white crystals, m.p.183°-186°C., yield, 1.3 g. Five recrystallizations from absolute ethanolgive product of constant specific rotation; [α]_(D) ²⁴.sup.° = + 18.75°.

The (+) tartrate is suspended in water and the mixture made basic withsaturated sodium carbonate solution. The oily base is extracted intohexane. Evaporation of the washed and dried hexane extract leaves the(+) base as the residual pale yellow oil; [α]_(D) ²⁴.sup.° = + 31.76°.

EXAMPLE 82 (-) α,N-Dimethyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine

α,N-Dimethyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine (-)-tartrateobtained by the procedure described in Example 81, 9.6 g. (0.0249 mole)is suspended in water and the mixture made basic with saturated sodiumcarbonate solution. The oily base is extracted into hexane. Evaporationof the washed and dried hexane extract leaves the base as the residualpale yellow oil. The base, 7.65 g. (0.0246 mole), is dissolved in 20 ml.of absolute ethanol and treated with a solution of 1.85 g. (0.0123 mole)of (+) tartaric acid in 20 ml. of absolute ethanol. Crystallization isinitiated by seeding and the solution is allowed to stand at roomtemperature until no further precipitation occurs. After collection ofthe (+) tartrate, the ethanolic mother liquor is evaporated to drynessunder reduced pressure and the residual solid suspended in water. Themixture is rendered alkaline with saturated sodium carbonate solutionand the oily base is extracted into hexane. Evaporation of the washedand dried hexane extract under reduced pressure leaves the (-) baseweighing 1.09 g.

The (-) base is dissolved in 4 ml. of absolute ethanol and treated witha solution of 262 mg. (0.00175 mole) of (-) tartaric acid in 2 ml. ofabsolute ethanol. The (-) tartrate separates in white crystals, m.p.184°-187°C.; yield, 1.1 g. Three recrystallizations from absoluteethanol give product of constant specific rotation; [α]_(D) ²³.5.sup.° =-21.82; m.p. 190°-192°C.

Anal. calc'd for C₁₇ H₁₇ F₄ N.1/2 C₄ H₄ O₆ : C,59.05; H,5.22; N,3.62.Found: C,59.25; H,5.30; N,3.49.

The (-) tartrate is suspended in water and the mixture made basic withsaturated sodium carbonate solution. The oily base is extracted intohexane. Evaporation of the washed and dried hexane extract leaves the(-) base as the residual pale yellow oil; [α]_(D) ²⁴.sup.° = -32.17.

EXAMPLE 83 α,α,α',α'-Tetrafluoroethylene- 2,2'-bis (benzylamine)

A. 2,2'-Dimethyl-α,α,α',α'-tetrafluorobibenzyl

o-Tolil, 4.76 g. (0.02 mole), together with 41 g. of sulfurtetrafluoride, 1.3 g. of mercury, about 1 g. of hydrogen fluoride and 40ml. of benzene, is charged into a stainless steel autoclave and heatedfor 10 hours at 80°C. After cooling and venting the vessel, the mixtureis separated from mercury and filtered. Evaporation of benzene from thefiltrate under reduced pressure leaves a brown residue that istriturated with hot cyclohexane and filtered. Evaporation of cyclohexanefrom the filtrate under reduced pressure leaves the product as a brownsolid. Sublimation at 105°C. and 0.05 mm. yields white crystals, m.p.71.5°-73.5°C. A sample for analysis melts at 73°-75°C. afterrecrystallization from hexane.

Anal. calc'd for C₁₆ H₁₄ F₄ : C,68.08; H,5.00. Found: C,67.76; H,5.00.

B. α,α,α',α'-Tetrafluoroethylene-2,2'-bis (benzyl bromide)

A mixture of 1.41 g. (0.005 mole) or2,2'-dimethyl-α,α,α',α'-tetrafluorobibenzyl, 1.78 g. (0.01 mole) ofN-bromosuccinimide, a trace of benzoyl peroxide, and 60 ml. of carbontetrachloride is stirred at reflux for 7 hours. After cooling, theprecipitate, a mixture of product and succinimide, is collected, dried,and triturated with 5% aqueous sodium hydroxide. The insoluble productis collected, washed with water, dried, and recrystallized from benzeneto give white crystals, m.p. 178°-183°C. Repeated recrystallization frombenzene affords the analytical sample, m.p. 184°-186°C.

Anal. calc'd for C₁₆ H₁₂ Br₂ F₄ : C,43.67; H,2.75. Found: C,43.94;H,2.77.

C. α,α,α',α'-Tetrafluoroethylene-2,2'-bis (benzylhexaminium bromide)

Hexamine, 6.44 g. (0.046 mole), is dissolved in 75 ml. of boilingchloroform; 10.1 g. (0.023 mole) ofα,α,α',α'-tetrafluoroethylene-2,2'-bis (benzyl bromide) is added and themixture is heated to refluxing for 8 hours. After cooling, theprecipitate is collected, washed with absolute ether, and dried to yieldwhite crystalline solid, m.p. 186°-190°C. dec.

D. α,α,α',α'-Tetrafluoroethylene-2,2'-bis (benzylamine)

A mixture of 17.2 g. (0.0239 mole) ofα,α,α',α'-tetrafluoroethylene-2,2'-bis (benzylhexaminium bromide), 25.6ml. of concentrated hydrochloric acid and 135 ml. of absolute ethanol isheated to refluxing for 9 hours. After cooling, the white precipitate isfiltered and the filtrate evaporated under reduced pressure. The residueand the precipitate are combined, dissolved in water, and the cooledsolution is made strongly basic with 40% aqueous sodium hydroxide. Thewhite solid product separates and is collected, washed with water andether, and dried by evaporation of a solution in benzene; m.p. 96°-97°C.An additional quantity of the product is recovered from the etherealwashings; m.p. 93°-95°C. An analytical sample melts at 98.5°-100°C.after sublimation in vacuo.

Anal. calc'd for C₁₆ H₁₆ F₄ N₂ : C,61.53; H,5.16; N,8.97. Found:C,61.15; H,5.09; N,8.83.

The (±) dilactate salt is prepared by treating a solution ofα,α,α',α'-tetrafluoroethylene-2,2'-bis (benzylamine) in isopropylalcohol with a slight excess of 85-90% (±) lactic acid. The (±)dilactate precipitates in white crystals, m.p. 180.5°-181.5°C. Repeatedrecrystallization from absolute ethanol-absolute methanol yields apurified sample; m.p. 186°-187.5°C.

Anal. calc'd for C₁₆ H₁₆ F₄ N₂.2 C₃ H₆ O₃ : C,53.66; H,5.73; N,5.69.Found: C,53.92; H,5.91; N,5.69.

EXAMPLE 84N,N-Dimethyl-3-(α,α,β,β-tetrafluorophenethyl)-o-xylene-α,α'-diamine

A. 2',3'-Dimethyl-2-phenylacetophenone

By following essentially the same procedures described in Example 1,2,3-dimethylbenzonitrile is reacted with benzylmagnesium chloride toyield 2,3-dimethylphenylbenzyl ketimine hydrochloride. Afterrecrystallization from absolute ethanol-absolute ether, the product isobtained as white crystals, m.p. 228.5°-229.5°C.

Anal. Calc'd for C₁₆ H₁₇ N.HCl: C,73.97; H,6.98; N,5.39. Found: C,73.49;H,6.89; N,5.29.

Hydrolysis of the ketimine hydrochloride by essentially the sameprocedure described in Example 1 gives2',3'-dimethyl-2-phenylacetophenone. After recrystallizations fromisopropyl alcohol and from methanol, the purified product is obtained asa white crystalline solid, m.p. 52°-53°C.

B. 2,3-Dimethylbenzil

By following essentially the same procedures described in Example 2,2',3'-dimethyl-2-phenylacetophenone is oxidized to 2,3-dimethylbenzil.The crystalline product is purified by repeated recrystallization fromabsolute methanol; m.p. 61.5°-62.5°C.

C. 2,3-Dimethyl-α,α,α',α'-tetrafluorobibenzyl

By following essentially the same procedures described in Example 83,2,3-dimethylbenzil is converted to2,3-dimethyl-α,α,α',α'-tetrafluorobibenzyl. The crude crystallineproduct is purified by sublimation at 95°C. and 0.05 mm.; m.p.110°-111.5°C. The analytical sample, m.p. 110°-111°C., is obtained byrecrystallization from hexane.

Anal. calc'd for C₁₆ H₁₄ F₄ : C,68.08; H,5.00; F,26.92. Found: C,68.16;H,5.16; F,26.63.

D. 3-(α,α,β,β-tetrafluorophenethyl)-o-xylene-α,.alpha.'-dibromide

A mixture of 6.13 g. (0.022 mole) of2,3-dimethyl-α,α,α',α'-tetrafluorobibenzyl, 7.85 g. (0.044 mole) ofN-bromosuccinimide, a catalytic amount of benzoyl peroxide, and 175 ml.of carbon tetrachloride is stirred at reflux for 6 hours. After cooling,the precipitate of succinimide is filtered and washed with carbontetrachloride. Evaporation of the filtrate under reduced pressure leavesthe product as a slightly oily white solid, m.p. 71°-83°C.Recrystallization from petroleum ether yields purified material, m.p.88°-92°C. A sample for analysis is sublimed at 85°C. and 0.02 mm.; m.p.90°-92°C.

Anal. calc'd for C₁₆ H₁₂ Br₂ F₄ : C,43.66; H,2.75. Found: C,43.78;H,2.74.

E. N,N-Dimethyl-3-(α,α,β,β-tetrafluorophenethyl)-o-xylene-α,α'-diamine

3-(α,α,β,β-tetrafluorophenethyl)-o-xylene-α,.alpha.'-dibromide, 2.0 g.(0.0045 mole), is added to about 15- 25 ml. of liquid methylamine cooledin a Dry Ice-chloroform bath. The solid dissolves and after 10 minutes,the cooling bath is removed and the solution is allowed to evaporate.The residual solid is triturated with benzene and the insolublemethylamine hydrobromide is removed by filtration. Evaporation of thebenzene filtrate under reduced pressure leaves the product as theresidual gummy solid.

The base is converted to the dihydrobromide salt by introducing gaseoushydrogen bromide into an ethanolic solution. Dilution with absoluteether precipitates the dihydrobromide that is recrystallized fromabsolute ethanol-absolute ether to obtain purified material, m.p.254°-256°C. A sample for analysis melts at 251°-253°C. afterrecrystallization from absolute ethanol.

Anal. calc'd for C₁₈ H₂₀ F₄ N₂. 2HBr: C,43.04; H,4.41; N,5.58; Br,31.83.Found: C,43.21; H,4.39; N,5.60; Br,31.64.

EXAMPLE 85N,N-Dibenzyl-3-(α,α,β,β-tetrafluorophenethyl)-o-xylene-α,α'-diamine

A solution of 2.2 g. (0.005 mole) of3-(α,α,β,β-tetrafluorophenethyl)-o-xylene-α,.alpha.'-dibromide and 1.7g. (0.016 mole) of benzylamine in 50 ml. of dry benzene is stirred atroom temperature for 15 minutes. During this period, a white precipitatebegins to separate; the mixture is heated to refluxing for 18 hours.After cooling, the precipitate of benzylamine hydrobromide is collectedand washed with benzene. Evaporation of the benzene filtrate leaves aviscous yellow oil as the residue that is triturated with boilingabsolute ether. The insoluble hydrobromide salt of the product iscollected and recrystallized from benzene-absolute ethanol-absoluteether to obtain white crystalline solid, m.p. 172°-174°C.Recrystallization from acetone affords the analytical sample, m.p.176°-177.5°C.

Anal. calc'd for C₃₀ H₂₈ F₄ N₂.HBR: C,62.81; H,5.10; N,4.89. Found:C,62.64; H,5.10; N,5.22.

EXAMPLE 86 4-(α,α,β,β-Tetrafluorophenethyl)-isoindoline

A. N-Benzyl-4-(α,α,β,β-tetrafluorophenethyl)-isoindolin

The ethereal filtrate remaining after collection ofN,N-dibenzyl-3-(α,α,β,β-tetrafluorophenethyl)-o-xylene-α,α'-diaminehydrobromide as described in Example 85 is evaporated to dryness invacuo leaving the crude product as the viscous, oily yellow base. Thehydrobromide salt is prepared by treating a methanolic solution of thebase with an equivalent of 48% aqueous hydrobromic acid. Dilution withabsolute ether precipitates the hydrobromide, m.p. 228°-231°C. A samplefor analysis is obtained as white crystals, m.p. 236.5°-238.5°C., afterrepeated recrystallization from absolute methanol-absolute ether andtreatment with decolorizing carbon.

Anal. calc'd for C₂₃ H₁₉ F₄ N.HBr: C,59.24; H,4.32; N,3.00. Found:C,58.84; H,4.30; N,3.05.

B. 4-(α,α,β,β-Tetrafluorophenethyl)-isoindoline

A solution of 1.63 g. (0.0035 mole) ofN-benzyl-4-(α,α,β,β-tetrafluorophenethyl)-isoindoline hydrobromide in160 ml. absolute ethanol-14 ml. absolute methanol is stirred with 320mg. of 5% palladium on carbon under hydrogen at atmospheric pressureuntil the absorption of hydrogen is complete. The catalyst is removed byfiltration and evaporation of the filtrate under reduced pressure leavesthe crystalline hydrobromide salt of the product, m.p. 191°-192°C., asthe residue. Recrystallizations from absolute ethanol-absolute ether,with treatment with decolorizing carbon, and from isopropyl alcoholafford the analytical sample, m.p. 192°-194°C.

Anal. calc'd for C₁₆ H₁₃ F₄ N.HBr: C,51.09; H,3.75; N,3.72. Found:C,50.94; H,3.78; N,3.83.

EXAMPLE 87 2-Methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzylamine

A. 2-Methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl bromide

A mixture of 4.0 g. (0.0142 mole) of2,3-dimethyl-α,α,α',α'-tetrafluorobibenzyl, 2.52 g. (0.0142 mole) ofN-bromosuccinimide, about 50 mg. of benzoyl peroxide, and 100 ml. ofcarbon tetrachloride is stirred at reflux for 21/2 hours. After cooling,the precipitate of succinimide is removed by filtration and the filtrateis evaporated to dryness under reduced pressure. The residual solid isrecrystallized from petroleum ether to yield the white crystallineproduct, m.p. 67°-71°C. Repeated recrystallization from petroleum etheraffords the analytical sample, m.p. 69°-71°C.

Anal. calc'd for C₁₆ H₁₃ BrF₄ : C,53.21; H,3.63; Br,22.12. Found:C,54.21; H,3.84; Br,21.38.

B. N-[2-Methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl]-phthalimide

A mixture of 8.02 g. (0.022 mole) of2-methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl bromide, 4.10 g. (0.022mole) of potassium phthalimide, and 40 ml. of dimethylformamide isstirred 30 minutes at room temperature, 4 hours at 95°C., and 3 hours atreflux. The cooled mixture is diluted with 100 ml. of chloroform andwashed with 150 ml. of water. After re-extraction of the aqueous layerwith chloroform, the combined organic extracts are washed with 0.1 N.sodium hydroxide, water, dried over anhydrous magnesium sulfate, andevaporated to dryness in vacuo. Recrystallization of the residual solidfrom isopropyl alchol affords the white crystalline product, m.p.135°-137°C.

C. 2-Methyl-3-(α,α,β ,β-tetrafluorophenethyl)-benzylamine

N-[2-Methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl]-phthalimide, 3.74g. (0.00876 mole), is dissolved in 100 ml. of boiling 95% ethanol.Hydrazine hydrate, 0.87 ml. of 100%, is added and the mixture is heatedto refluxing for 7 hours. Upon cooling and standing, a voluminous whiteprecipitate of phthalhydrazide separates and is removed by filtration.Evaporation of the ethanolic filtrate to approximately one-half volumeyields additional precipitate of phthalhydrazide that is removed byfiltration. The filtrate then is cooled in an ice-bath, acidified to pH2with about 1.5 ml. of concentrated hydrochloric acid, and evaporated todryness under reduced pressure. The residual solid is dissolved in 25ml. of absolute ethanol. Dilution of the solution with about 15 ml. ofabsolute ether yields additional precipitate of phthalhydrazide that isfiltered. Concentration of the filtrate to a volume of about 15 ml. anddilution with 25 ml. of absolute ether precipitates the hydrochloridesalt of the product as shiny white plates, m.p. 199.5°-201°C. Repeatedrecrystallizations from absolute ethanol-absolute ether afford thepurified hydrochloride, m.p. 209°-211.5°C.

Anal. calc'd for C₁₆ H₁₅ F₄ N.HCl: C,57.58; H,4.83; N,4.20. Found:C,57.28; H,4.83; N,4.12.

EXAMPLE 88 α,α-Dimethyl-3-(α,α,β,β-tetrafluorophenethyl)-benzylamine

A. 3'-Bromo-2-phenylacetophenone

By following essentially the same procedures described in Example 1,3-bromobenzonitrile is reacted with benzylmagnesium chloride to yield3-bromophenyl benzyl ketimine hydrochloride. This salt is obtained as anoily solid that is hydrolyzed directly without purification byessentially the same procedure described in Example 1. The crude3'-bromo-2-phenylacetophenone, an oily solid, is distilled in vacuo,collecting the pale yellow solid product over a range of 143°-155°C./0.1mm. The fraction boiling at 150°-155°C./0.1 mm. is recrystallized fromhexane to obtain the analytical sample as white crystals, m.p. 62°-64°C.

Anal. calc'd for C₁₄ H₁₁ BrO: C,61.11; H,4.03. Found: C,61.25; H,4.00.

B. 3-Bromobenzil

By following essentially the same procedures described in Example 2,3'-bromo-2-phenylacetophenone is oxidized to 3-bromobenzil. The oilyproduct is purified by vacuum distillation; b.p. 148°-155°C./0.05 mm.The distillate solidifies to yellow crystals, m.p. 78°-82°C. and asample for analysis is obtained by recrystallization from hexane; m.p.81°-82.5°C.

Anal. calc'd for C₁₄ H₉ BrO₂ : C,58.15; H,3.13. Found: C,57.81; H,3.05.

C. 3-Bromo-α,α,α',α'-tetrafluorobibenzyl

By following essentially the same procedures described in Example 83,3-bromobenzil is converted to 3-bromo-α,α,α',α'-tetrafluorobibenzyl. Thecrude crystalline product is purified by sublimation at 65°C. and 0.02mm.; m.p. 72°-75°C. The analytical sample, m.p. 74°-76°C, is obtained byrecrystallization from petroleum ether.

Anal. calc'd for C₁₄ H₉ BrF₄ : C, 50.47; H,2.72. Found: C,50.51; H,2.57.

D. 2-[3-(α,α,β,β-Tetrafluorophenethyl)-phenyl]-propanol-2

The Grignard reagent, 3-(α,α,β,β-tetrafluorophenethyl)-phenylmagnesiumbromide, is prepared as follows. In a nitrogen atmosphere, magnesiumturnings, 0.72 g. (0.0297 g. atom), are covered with 6 ml. of absoluteether; a crystal of iodine is added and a few ml. of a solution of 8.97g. (0.027 mole) of 3-bromo-α,α,α',α'-tetrafluorobibenzyl in 30 ml. ofabsolute ether are introduced. The mixture is stirred and heated torefluxing; a few drops of a solution of 0.2 g. of ethylene bromide in 1ml. of absolute ether are added. Dropwise addition of the remainingsolution of the bromide is begun and stirring at reflux is continued forseveral hours after the formation of the Grignard adduct is initiated.During this period, several additions of a total of 0.1 g. of freshlycut piecces of magnesium and the remainder of the ethylene bromidesolution are made.

The solution of the Grignard reagent is cooled in an ice-bath and asolution of 3.5 g. (0.06 mole) of acetone in 5 ml. of absolute ether isadded dropwise.

After stirring at room temperature and in a nitrogen atmosphereovernight, the mixture is cooled in an ice-bath and hydrolyzed by thedropwise addition of 2 ml. of water. The ethereal solution is decantedfrom the gelatinous precipitate that is re-extracted several times withether. The combined, washed and dried, ethereal extracts are evaporatedunder reduced pressure, leaving the crude product as the residual solid.Purification is effected by column chromatography on 200 g. of silicagel, the product being eluted with benzene. The fractions which shownone spot of Rf 0.2 on a silica thin layer plate developed withchloroform are combined. Evaporation of the solvent under reducedpressure leaves the white crystalline product. A sample for analysis isrecrystallized from hexane; m.p. 76°-78°C.

Anal. calc'd for C₁₇ H₁₆ F₄ O: C,65.37; H,5.16. Found: C,65.54; H, 5.15.

E. N-[α,α-Dimethyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide

Glacial acetic acid, 6 ml., is stirred and cooled in an ice-bath untilit is half-solid; sodium cyanide, 1.08 g. (0.022 mole) is added inportions, keeping the temperature to 15°-20°C. An ice-cold solution of5.4 g. of concentrated sulfuric acid in 2.8 ml. of glacial acetic acidis added slowly, keeping the temperature at 10°-20°C. After stirring for10 minutes, the ice-bath is removed and a solution of 5.58 g. (0.01785mole) of 2-[3-(α,α,β,β-tetrafluorophenethyl) phenyl]-propanol-2 in 3 ml.of glacial acetic acid is introduced. Stirring is continued at 25°C. for9 hours. The reaction mixture is poured into about 80 ml. of ice andwater and neutralized by the addition of solid sodium carbonate. Theoily product is extracted into ether. Evaporation of the washed anddried ethereal extract leaves the product as the residual oily solid.Purification is effected by column chromatography on 200 g. of silicagel, the product being eluted with chloroform. The fractions which showone spot of Rf 0.1 on a silica thin layer plate developed withchloroform are combined. Evaporation of the solvent under reducedpressure leaves the white crystalline product, m.p. 90°-95°C.

F. α,α-Dimethyl-3-(α,α,β,β-tetrafluorophenethyl)-benzylamine

A solution of 2.62 g. (0.0077 mole) ofN-[α,α-dimethyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide in 56ml. glacial acetic acid-35 ml. water-5.6 ml. concentrated hydrochloricacid is stirred at reflux for 6 hours. Evaporation of the solvents underreduced pressure leaves the hydrochloride salt of the product as thewhite crystalline residue. Recrystallization from absolutemethanol-absolute ether affords the purified hydrochloride, m.p.179°-180°C. The melting point is unchanged by recrystallization fromabsolute methanol-absolute ether.

Anal. calc'd for C₁₇ H₁₇ F₄ N.HCl: C,58.71; H,5.22; N,4.02. Found:C,58.93; H,5.58; N,3.85.

EXAMPLE 89 4-(α,α,β,β-Tetrafluorophenethyl)-benzylamine

A. 4-Bromo-α,α,α',α'-tetrafluorobibenzyl

By following essentially the same procedures described in Example 3,4-bromobenzil is converted to 4-bromo-α,α,α',α'-tetrafluorobibenzyl. Thecrude crystalline product is purified by sublimation at 70°-75°C. and0.02 mm.; m.p. 80°-82°C. A sample for analysis, m.p. 82°-83.5°C., isobtained by resublimation.

Anal. calc'd for C₁₄ H₉ BrF₄ : C,50.49; H,2.72; Br,24.00. Found:C,50.51; H,2,81; Br,23.78.

B. 4-(α,α,β ,β-Tetrafluorophenethyl)-benzonitrile

By following essentially the same procedures described in Example 4,4-bromo-α,α,α',α'-tetrafluorobibenzyl is converted to4-(α,α,β,β-tetrafluorophenethyl)-benzonitrile. The crude crystallineproduct is purified by sublimation at 85°C. and 0.02 mm.; m.p.118°-123°C. Resublimation affords almost white solid, m.p. 120.5°-123°C.A sample for analysis is recrystallized from hexane and resublimed; m.p.123.5°-125.5°C.

Anal. calc'd for C₁₅ H₉ F₄ N: C,64.52; H,3.25; N,5.02. Found: C,64.76;H,3.37; N,4.80.

C. 4-(α,α,β,β-Tetrafluorophenethyl)-benzylamine

By following essentially the same procedures described in Example 5,4-(α,α,β,β-tetrafluorophenethyl)-benzonitrile is reduced to4-(α,α,β,β-tetrafluorophenethyl)-benzylamine. The white crystallineproduct, m.p. 99.5°-102°C., is purified by sublimation at 90°C. and 0.01mm.; m.p. 101°-103°C.

Anal. calc'd for C₁₅ H₁₃ F₄ N: C,63.57; H,4.62; N,4.94. Found: C,63.66;H,4.80; N,4.97.

The base may be converted to the hydrochloride salt by treating asolution in ethanol with a slight excess of ethanolic hydrogen chloride.The hydrochloride separates in white flakes, m.p. 252°-253°C. Themelting point is unchanged by further recrystallization from ethanol.

Anal. calc'd for C₁₅ H₁₃ F₄ N.HCl: C,56.35; H,4.41; N,4.38. Found:C,56.37; H,4.48; N,4.35.

EXAMPLE 90 α-Methyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine

A. 4'-(α,α,β,β-Tetrafluorophenethyl)-acetophenone

A solution of 3.3 g. (0.0118 mole) of4-(α,α,β,β-tetrafluorophenethyl)-benzonitrile in 25 ml. of dry,peroxidefree tetrahydrofuran is added dropwise to a stirred solution ofabout 0.03 mole of methylmagnesium bromide in 25 ml. of absolute etherin a nitrogen atmosphere. The mixture is stirred at reflux for about 26hours. After cooling in an ice-bath, the adduct is hydrolyzed by thedropwise addition of about 5 ml. of water and the mixture is dilutedwith about 50 ml. of ether. The organic phase is decanted and thegelatinous precipitate is washed thoroughly with ether. The combinedethereal extracts are washed once with water, extracted with 15 ml. ofice-cold 6N hydrochloric acid in several portions, and then washed withwater and dried over anhydrous sodium sulfate. Evaporation of thesolvent under reduced pressure leaves the product as the oily solidresidue. Sublimation at 95°-100°C. and 0.02 mm. gives purified materialas white crystals, m.p. 128°-133°C. A sample for analysis, m.p.134°-135.5 °C., is obtained by repeated recrystallization from hexaneand resublimation.

Anal. calc'd for C₁₆ H₁₂ F₄ O: C,64.86; H,4.08; F,25.65. Found: C,65.09;H,4.31; F,25.23.

B. 4'-(α,α,β,β-Tetrafluorophenethyl)-acetophenone oxime

A solution of 1.1 g. (0.00372 mole) of4'-(α,α,β,β-tetrafluorophenethyl)-acetophenone, 0.7 g. (0.0071 mole) ofhydroxylamine hydrochloride, 8.5 ml. of absolute ethanol, and 1.5 ml. ofdry pyridine is heated to refluxing for 6 hours. Solvents are evaporatedunder reduced pressure and the residual solid is triturated with water.The crystalline product, m.p. 137°-139°C., is collected andrecrystallized from hexane to obtain white needles, m.p. 139°-141°C.Recrystallization from hexane affords the analytical sample, m.p.140°-141°C.

Anal. calc'd for C₁₆ H₁₃ F₄ NO: C,61.73; H,4.21; N,4.50. Found: C,61.90;H,4.20; N,4.50.

C. α-Methyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine

A solution of 2.45 g. (0.00787 mole) of4'-(α,α,β,β-tetrafluorophenethyl)-acetophenone oxime in 47 ml. absoluteethanol-3 ml. 8N hydrogen chloride in ethanol is stirred with 1.0 g. of5% palladium on carbon under hydrogen at atmospheric pressure and 27°C.until the absorption of hydrogen is complete. The catalyst is removed byfiltration and evaporation of the filtrate under reduced pressure leavesa residual solid that is triturated with benzene and ether. Theinsoluble hydrochloride salt of the product is collected; m.p.210°-213°C. Repeated recrystallizations from ethanol-ether, acetone, andcold methanol-ether afford the purified hydrochloride, m.p. 216°-217°C.The salt is suspended in water, the ice-cold mixture made strongly basicwith 5% aqueous sodium hydroxide and the base extracted into benzene.Evaporation of the washed and dried benzene extract leaves the productas the residual white crystalline solid, m.p. 63.5°-66°C. A sample foranalysis is sublimed at 60°C. and 0.05 mm.; m.p. 64.5°-66°C.

Anal. calc'd for C₁₆ H₁₅ F₄ N: C,64.65; H,5.09; N,4.71. Found: C,64.55;H,5.07; N,4.72.

The base may be reconverted to the hydrochloride salt by treating asolution in methanol with a slight excess of 8N hydrogen chloride inethanol. Dilution with absolute ether precipitates the white crystallinehydrochloride, m.p. 215°-217°C. Recrystallization from methanol-etheraffords the analytical sample, m.p. 218°-219°C.

Anal. calc'd for C₁₆ H₁₅ F₄ N.sup.. HCl: C,57.58; H,4,83; N,4.20. Found:C,57.22; H,4.75; N,4.15.

EXAMPLE 91 α,α-Dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine

A. 2-[4-(α,α,β,β-Tetrafluorophenethyl)-phenyl]-propanol-2

By following essentially the same procedures described in Example 88,4-(α,α,β,β-tetrafluorophenethyl)-phenylmagnesium bromide is preparedfrom 4-bromo-α,α,α',α'-tetrafluorobibenzyl and reacted with acetone toyield 2-[4-(α,α,β,β,-tetrafluorophenethyl)-pehnyl]-propanol-2.Purification of the crude, oily solid product is effected by columnchromatography on silica gel, the product being eluted with chloroform.The fractions that show one spot of Rf 0.25 on a fluorescent silica thinlayer plate developed with chloroform are combined. Evaporation of thesolvent under reduced pressure leaves the white crystalline product,m.p. 60°-62°C. A sample for analysis is sublimed at 60°C. and 0.02 mm.;m.p. 62°-63.5°C.

Anal. calc'd for C₁₇ H₁₆ F₄ O: C,65.37; H,5.16; F,24.33. Found: C,65.46;H,5.19; F,24.52.

B. 2-[4-(α,α,β,β-Tetrafluorophenethyl)-phenyl]-propanol-2

A solution of 500 mg. (0.00169 mole) of4'-(α,α,β,β-tetrafluorophenethyl)-acetophenone in 18 ml. of absoluteether is added dropwise to a stirred solution of about 0.00189 mole ofmethylmagnesium bromide in 5 ml. of absolute ether at room temperatureand in a nitrogen atmosphere. After 4 hours at reflux and an overnightperiod at room temperature, the mixture is cooled in an ice-bath andhydrolyzed by the dropwise addition of 4 ml. of water. After filtration,the ethereal layer is separated from the filtrate, washed with water,and dried over anhydrous magnesium sulfate. Evaporation of the solventunder reduced pressure leaves the crystalline product as the residue.Sublimation at 67°C. and 0.02 mm. gives purified material, m.p.54°-60°C.

C. N-[α,α-Dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide

By following essentially the same procedures described in Example 88,2-[4-(α,α,β,β-tetrafluorophenethyl)-phenyl]-propanol-2 is converted viathe Ritter reaction toN-[α,α-dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide. Thecrude oily solid mixture is separated by column chromatography on silicagel, the product being eluted with chloroform and 2% methanol inchloroform. The fractions that show one spot of Rf 0.17 on a fluorescentsilica thin layer plate developed with chloroform are combined.Evaporation of the solvent under reduced pressure leaves the whitecrystalline product, m.p. 115.5°-117°C. Recrystallization from absoluteether-petroleum ether affords the analytical sample, m.p. 116.5°-118°C.

Anal. calc'd for C₁₈ H₁₇ F₄ NO: C,63.71; H,5.05; N,4.13. Found: C,63.96;H,4.83; N,4.01.

D. 2-[4-(α,α,β,β-Tetrafluorophenethyl)-phenyl]-propene

Column chromatography on silica gel of the crude oily solid mixtureobtained from the Ritter reaction on2-[4-(α,α,β,β-tetrafluorophenethyl)-phenyl]-propanol-2 as describedabove in Example 91-C affords2-[4-(α,α,β,β-tetrafluorophenethyl)-phenyl]-propene as the secondcomponent. The fractions showing a major component at the solvent fronton a fluorescent silica thin layer plate developed with chloroform arecombined. Evaporation of the solvent under reduced pressure leaves thewhite crystalline product, m.p. 97°-104°C. Sublimation at 80°C and 0.02mm. affords a purified sample, m.p. 106.5°-111°C.

Anal. calc'd for C₁₇ H₁₄ F₄ : C,69.38; H,4.79. Found: C,69.58; H,4.83.

E. N-[α,α-Dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide

By following essentially the same procedures described in Example 88,2-[4-(α,α,β,β-tetrafluorophenethyl)-phenyl]-propene is converted via theRitter reaction toN-[α,α-dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide. Thepurified product, m.p. 115°-119°C., is obtained by column chromatographyon silica gel of the crude material as described above in Example 91-C.

F. α,α-Dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine

By following essentially the same procedures described in Example 88,N-[α,α-dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide ishydrolyzed to α,α-dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine.The hydrochloride salt of the product, m.p. 271.5°-272.5°C., isisolated. Repeated recrystallizations from absolute ethanol-absoluteether afford the purified hydrochloride, m.p. 274°-275°C.

Anal. calc'd for C₁₇ H₁₇ F₄ N.sup.. HCl: C,58.71; H,5.22; N,4.02. Found:C,58.55; H,5.26; N,4.09.

EXAMPLE 92 4-(α,α,β,β-Tetrafluorophenethyl)-α,α,N-trimethylbenzylamine

By following essentially the same procedures described in Example 6,N-[α,α-dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide isreduced to 4-(α,α,β,β-tetrafluorophenethyl)-α,α,N-trimethylbenzylamine.The crude base is converted to the dihydrogen citrate salt by treating asolution in isopropyl alcohol with a solution of a molar equivalent ofcitric acid in isopropyl alcohol. Dilution with absolute etherprecipitates the dihydrogen citrate as white crystals, m.p. 169°-170°C.dec. Recrystallization from absolute ethanol-absolute methanol gives apurified sample, m.p. 166°-168°C.

Anal. calc'd for C₁₈ H₁₉ F₄ N.sup.. C₆ H₈ O₇ : C,55.70; H,5.26; N,2.71.Found: C,55.82; H,5.23; N,2.53.

The base may be purified by sublimation at 80°C. and 0.02 mm. to yieldwhite crystals, m.p. 65°-80°C. The purified base is converted to thehydrochloride salt by treating a solution in absolute ether with aslight excess of 8.2N hydrogen chloride in ethanol. The hydrochloride,m.p. 203°-205°C., precipitates. A sample for analysis, m.p. 206°-208°C.,is obtained by repeated recrystallization from ethanol.

Anal. calc'd for C₁₈ H₁₉ F₄ N.sup.. HCl: C,59.76; H,5.57; N,3.87. Found:C,59.92; H,5.55; N,3.68.

EXAMPLE 934-(α,α,β,β-Tetrafluorophenethyl)-α,α,N,N-tetramethylbenzylamine

A solution of 5.8 g. (0.0167 mole) ofα,α-dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine hydrochloridein 8 ml. of 88% formic acid is treated with 3 g. (0.1 mole) of 37%formaldehyde and the stirred mixture is heated in an oil bath at 95°C.overnight. After the addition of 5 ml. of concentrated hydrochloric acidto the cooled mixture, the solution is evaporated to dryness underreduced pressure. The residual syrup is dissolved in 120 ml. of waterand the solution is rendered strongly alkaline with 40% aqueous sodiumhydroxide. The base is extracted into benzene. Evaporation of the washedand dried benzene extract under reduced pressure leaves the product asthe residual oil; 6.7 g. This product is shown to contain unreactedstarting material by thin layer chromatographic comparison to anauthentic sample. The base is converted to the mixed hydrochloride saltsby treating a solution in isopropyl alcohol with a slight excess of 8.2Nhydrogen chloride in ethanol. Dilution with ether precipitates themixture of hydrochlorides, m.p. 182°-190°C. This material is combinedwith a similar mixture from a previous experiment and a solution of the7.75 g. in 13.3 ml. of 88% formic acid is treated with 5.3 g. of 37%formaldehyde. The stirred mixture is heated in an oil bath at 95°C. forabout 21/2 days. Work-up by the procedure described above affords theoily base that is converted to the hydrochloride salt by the proceduredescribed above to yield white crystals, m.p. 171°-173.5°C.Recrystallization from isopropyl alcohol gives the analytical sample,m.p. 174°-175.5°C.

Anal. calc'd for C₁₉ H₂₁ F₄ N.sup.. HCl: C,60.72; H,5.90; N,3.72. Found:C,60.90; H,5.75; N,3.84.

EXAMPLE 944-(p-Methyl-α,α,β,β-tetrafluorophenethyl)-α,.alpha.,N-trimethylbenzylamine

A. 4-Bromo-4'-methylbenzoin

A solution of 67 g. (0.314 mole) of p-bromophenyl-glyoxal in 300 ml. ofdry toluene is added dropwise over 1 1/2 hours to a stirred suspensionof 84 g. (0.6 mole) of anhydrous aluminum chloride in 1.25 l. of drytoluene cooled in an ice-bath. Stirring in the cold is continued for 5hours and the mixture then is held at 5°-10°C. overnight. The mixture ispoured into about 2 l. of ice and 6N hydrochloric acid. The aqueousphase is separated and re-extracted with three portions of benzene. Thecombined, washed and dried organic extracts are concentrated underreduced pressure to a volume of about 200 ml. Dilution with 150 ml. ofpetroleum ether precipitates the white crystalline product, m.p.80°-82°C. Repeated recrystallization from 60% ethanol affords theanalytical sample, m.p. 82°-83.5°C.

Anal. calc'd for C₁₅ H₁₃ BrO₂ : C,59.02; H,4.29; Found: C,59.18; H,4.27.

B. 4-Bromo-4'-methylbenzil

Cupric sulfate, 90 g. (0.36 mole), is stirred and heated on thesteam-bath with 110 ml. of pyridine and 45 ml. of water until completesolution is obtained. 4-Bromo-4'-methylbenzoin, 55 g. (0.18 mole), isadded and the mixture is stirred and heated on the steam-bath for 3hours. During this period, the yellow crystalline product separates.After cooling and dilution with water, the product is collected, washedwith water, 1 N hydrochloric acid, and water, and dried; m.p.132°-135°C. The analytical sample is obtained as yellow needles, m.p.136°-137°C, after repeated recrystallizations from 95% ethanol.

Anal. calc'd for C₁₅ H₁₁ BrO₂ : C,59.41; H,3.66. Found: C,59.49; H,3.59.

C. 4-Bromo-4'-methyl-α,α,α',α'-tetrafluorobibenzyl

By following essentially the same procedures described in Example 83,4-bromo-4'-methylbenzil is converted to4-bromo-4'-methyl-α,α,α',α'-tetrafluorobibenzyl. The crude crystallineproduct is purified by sublimation at 90°C. and 0.05 mm.; whilecrystals, m.p. 103.5°-105.5°C. A sample for analysis is resublimed.

Anal. calc'd for C₁₅ H₁₁ BrF₄ : C,51.88; H,3.19; Br,23.01. Found:C,51.87; H,3.18; Br,23.14.

D. 2-[4-(p-Methyl-α,α,β,β-tetrafluorophenethyl)-phenyl]-propanol-2

By following essentially the same procedures described in Example 88,4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-phenyl-magnesium bromide isprepared from 4-bromo-4'-methyl-α,α,α',α'-tetrafluorobibenzyl andreacted with acetone to yield2-[4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-phenyl]-propanol-2.Purification of the crude oily solid product is effected by columnchromatography on silica gel, the product being eluted with chloroform.The fractions that show one spot of Rf 0.25 on a fluorescent silica thinlayer plate developed with chloroform are combined. Evaporation of thesolvent under reduced pressure leaves the pale yellow solid product,m.p. 83°-88°C. A sample for analysis is obtained as white crystals, m.p.88°-90°C., by sublimation at 80°C. and 0.05 mm. and recrystallizationfrom petroleum ether.

Anal. calc'd for C₁₈ H₁₈ F₄ O: C,66.25; H,5.56; F,23.29. Found: C,66.18;H,5.50; F,23.33.

E. N-[α,α-Dimethyl-4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide

By following essentially the same procedures described in Example 88,2-[4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-phenyl]-propanol-2 isconverted via the Ritter reaction toN-[α,α-dimethyl-4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide.The crude solid mixture is separated by column chromatography on silicagel, the product being eluted with chloroform and 2% methanol inchloroform. The fractions showing one major spot at Rf 0.15 on afluorescent silica thin layer plate developed with chloroform arecombined. Evaporation of solvent under reduced pressure leaves the paleyellow crystalline product, m.p. 109°-119°C. A sample for analysis, m.p.121°-122.5°C., is obtained by recrystallizations from ethanol-water andether-petroleum ether.

Anal. calc'd for C₁₉ H₁₉ F₄ NO: C,64.58; H,5.42; N,3.96. Found: C,64.34;H,5.35; N,3.76.

F.4-(p-Methyl-α,α,β,β-tetrafluorophenethyl)-α,.alpha.,N-trimethylbenzylamine

By following essentially the same procedures described in Example 6,N-[α,α-dimethyl-4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-benzyl]-formamideis reduced to4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-α,.alpha.,N-trimethylbenzylamine.The crude oily base is converted to the hydrochloride salt by treating asolution in ethanol with a slight excess of 8N hydrogen chloride inethanol. Dilution with absolute ether precipitates the white crystallinehydrochloride, m.p. 189°-190°C. The melting point is unchanged byrecrystallization from isopropyl alcohol-ether.

Anal. calc'd for C₁₉ H₂₁ F₄ N.sup.. HCl: C,60.72; H,5.90; N,3.73. Found:C,61.12; H,5.81; N,3.61.

EXAMPLE 95

α,α-Dimethyl-4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-benzylamine

By following essentially the same procedures described in Example 88,N-[α,α-dimethyl-4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-benzyl]-formamideis hydrolyzed toα,α-dimethyl-4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-benzylamine. Thehydrochloride salt of the product, m.p. 254.5°-256.5°C., is isolated.Recrystallization from absolute ethanol affords a purified sample, m.p.256°-258°C.

Anal. calc'd for C₁₈ H₁₉ F₄ N.sup.. HCl: C,59.75; H,5.57; N,3.87. Found:C,59.70; H,5.59; N,3.90.

EXAMPLE 96

2-Amino-4-methyl-N-[2-(α,α,β,β-tetrafluorophenethyl)-benzyl]-valeramide

In a nitrogen atmosphere, 3.7 g. (0.0146 mole) of Woodward's K reagentis stirred in 25 ml. of freshly distilled, dry acetonitrile and themixture is cooled to -5°C. in an ice-salt bath. A solution of 3.9 g.(0.0146 mole) of N-carbobenzoxy-L-leucine and 1.5 g. (0.0146 mole) oftriethylamine in 40 ml. of acetonitrile is added dropwise at a rate suchthat the temperature remains at -5 to 0°C. The mixture is stirred for 55min. below 0°C. and then for 1 hour at room temperature. After againcooling the solution to -5°C., a solution of 2.75 g. (0.0097 mole) of2-(α,α,β,β-tetrafluorophenethyl)-benzylamine in 12 ml. of acetonitrileis added dropwise. The mixture is stirred for 1 hour below 0°C., 3 hoursat room temperature, and then is allowed to stand at room temperature.

After evaporation of the solvent at room temperature under reducedpressure, the residual viscous, yellow oil is partitioned betweenmethylene chloride and water made slightly basic with a few drops of 40%aqueous sodium hydroxide. The methylene chloride extract is washed withwater, 1N hydrochloric acid, water, and dried over anhydrous sodiumsulfate. Evaporation of the solvent under reduced pressure leaves theN-carbobenzoxy derivative of the product as the residual yellow oil.

A solution of 6.6 g. of the oily N-carbobenzoxy derivative in 60 ml. ofabsolute ethanol is shaken with hydrogen at atmospheric pressure androom temperature over 2 g. of 5% palladium-charcoal until the absorptionof hydrogen is complete. The catalyst is removed by filtration andevaporation of the solvent under reduced pressure leaves the product asthe residual pale yellow oil. The base is converted to the hydrogenfumarate salt by treating a solution in absolute ether with a solutionof an excess of fumaric acid in absolute ethanol. Further dilution withether precipitates2-amino-4-methyl-N-[2-α,α,β,β-tetrafluorophenethyl)-benzyl]-valeramidehydrogen fumarate as white crystals, m.p. 137°-140°C. dec. Repeatedrecrystallization from methanol-ether affords a purified sample, m.p.140.5°-141.5°C. dec.

Anal. calc'd for C₂₁ H₂₄ F₄ N₂ O.C.sub. 4 H₄ O₄ : C,58.59; H,5.51;N,5.47. Found: C,58.74; H,5.50; N,5.50.

EXAMPLE 97

Salts of α,α-dimethyl-4(α,α,β,β-tetrafluorophenethyl)-benzylamine

A. α,α-Dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine-isethionate

Sodium isethionate, 15 g. (0.1 mole), was dissolved in 50 ml. of waterand the solution applied to a thoroughly washed column of approximately160 g. of organic strong acid cation exchanger in the hydrogen form(also known as Rexyn 101(H). The column was eluted with water until theeluant, a total of 400 ml., was approximately at pH 5.5. The eluant wasconcentrated in vacuo to a volume of about 50 ml. and the concentrationof isethionic acid in the solution was determined by potentiometrictitration to be 3.8M.

α,α-Dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine, 4.1 g.(0.0132 mole), was dissolved in 20 ml. of isopropyl alcohol and thesolution treated with 3.7 ml. of 3.8M isethionic acid. Crystallizationof the isethionate started after dilution with 400 ml. of absoluteether. The product was collected after several hours at roomtemperature, washed with absolute ether, and dissolved in 300 ml. ofbenzene. Water was removed azeotropically by distilling 200 ml. ofbenzene. The product was precipitated from the residual solution bydilution with 200 ml. of absolute ether; 5.8 g., m.p. 134.5°-136°.Recrystallization from 50 ml. of isopropyl alcohol - 200 ml. of absoluteether gave m.p. 135°-136.5°.

Anal. Calc'd. for C₁₇ H₁₇ F₄ N.C.sub. 2 H₆ O₄ S: C, 52.17; H, 5.30; N,3.20; S, 7.51. Found: C, 52.33; H, 5.31; N, 3.10; S, 7.41.

The following physical data have been determined onα,α-dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine isethionate:

Solubility in H₂ O: >400 mg./ml.

pH of 1% Solution in H₂ O: 4.7

B. α,α-Dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine-(±) lactate

α,α-Dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine hydrochloride,6.0 g. (0.0172 mole), was suspended in saturated sodium carbonate andthe base extracted into hexane. The combined hexane extracts were washedthoroughly with water and dried over anhydrous magnesium sulfate.Evaporation of the solvent under reduced pressure left 5.3 g. of thewhite crystalline base, m.p. 82°-84°.

A solution of the base (0.017 mole) in 25 ml. of acetone was treatedwith a solution of 1.85 g. (0.0175 mole) of 85-90% (±) lactic acid in 5ml. of acetone. Crystallization of the lactate started slowly afterdilution with 125 ml. of absolute ether. The product was collected after5 hours at room temperature and 16 hours of cooling at about 0°C.; 6.5g. (95%), m.p. 146°-148°. Recrystallization from 30 ml. of acetone - 125ml. of absolute ether gave a first crop of 4.75 g., m.p. 146°-148°.

Anal. Calcd. for C₁₇ H₁₇ F₄ N.C.sub. 3 H₆ O₃ : C, 59.84; H, 5.78; N,3.49. Found: C, 59.78; H, 5.75; N, 3.36.

C. Other salts ofα,α-dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine

A solution of the baseα,α-dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine dissolved inisopropyl alcohol was titrated with an equivalent amount of the desiredacid to form the salt which precipitates from solution completely onaddition of an equal volume of ether. The precipitated salt is thenfiltered from solution and dried. The following table represents thesalts prepared with physical constants:

    __________________________________________________________________________    Reagents and Salts                                                            __________________________________________________________________________    Free Base    Acid Reagent                                                                          Salt                                                     __________________________________________________________________________    A. α,α-Dimethyl-4-                                                             Maleic  α,α-Dimethyl-4-(α,α,β,.b                         eta.-                                                       (α,α,β,β-tetra-                                                           tetrafluorophenethyl)-                                      fluorophenethyl)- benzylamine hydrogen                                        benzylamine       maleate                                                  B. "         Citric  α,α-Dimethyl-4-(α,α,β,.b                         eta.-                                                                         tetrafluorophenethyl)-                                                        benzylamine dihydrogen                                                        citrate                                                  C. "         Tartaric                                                                              α,α-Dimethyl-4-(α,α,β,.b                         eta.-                                                                         tetrafluorophenethyl)-                                                        benzylamine (+) hydrogen                                                      tartrate                                                 D. "         Phosphoric                                                                            α,α-Dimethyl-4-(α,α,β,.b                         eta.-                                                                         tetrafluorophenethyl)-                                                        benzylamine dihydrogen                                                        phosphate hydrate                                        E. "         Sulfuric                                                                              α,α-Dimethyl-4-(α,α,β,.b                         eta.-                                                                         tetrafluorophenethyl)-                                                        benzylamine sulfate                                                           trihydrate                                               F. "         Methane α,α-Dimethyl-4-(α,α,β,.b                         eta.-                                                                 sulfonic                                                                              tetrafluorophenethyl)-                                                        benzylamine methane                                                           sulfonate                                                __________________________________________________________________________                       Anal.                                                                 C       H       N                                                  Melting Point                                                                            Calcd.                                                                            Found                                                                             Calcd.                                                                            Found                                                                             Calcd.                                                                            Found                                          __________________________________________________________________________    A.                                                                              160-161°                                                                        59.01                                                                             59.43                                                                             4.95                                                                              5.10                                                                              3.28                                                                              3.20                                           B.                                                                              165-166°                                                                        54.87                                                                             54.87                                                                             5.01                                                                              5.15                                                                              2.78                                                                              2.58                                           C.                                                                              185-187°dec.                                                                    54.66                                                                             54.60                                                                             5.02                                                                              5.46                                                                              3.04                                                                              2.76                                           D.                                                                              251-253°                                                                        53.96                                                                             53.51                                                                             5.46                                                                              5.21                                                                              3.70                                                                              3.71                                           E.                                                                              209.5-211.5°                                                                    52.70                                                                             52.51                                                                             5.46                                                                              5.00                                                                              3.62                                                                              3.52                                           F.                                                                              206.5-211.5°                                                                    53.06                                                                             53.22                                                                             5.20                                                                              5.32                                                                              3.44                                                                              3.32                                           __________________________________________________________________________

What is claimed:
 1. Compounds having the formula ##SPC9##wherein X andX' are selected from the group consisting of hydrogen, an alkyl grouphaving up to 6 carbon atoms, an alkenyl group having up to 6 carbonatoms, a perfluoroalkyl group having up to 4 carbon atoms, a phenyl or asubstituted phenyl radical, amino, an alkylamino group having up to 4carbon atoms, a dialkylamino group having up to 8 carbon atoms,fluorine, chlorine, bromine, iodine, hydroxyl, an alkoxyl group havingup to 4 carbon atoms and a perfluoroalkoxyl group having up to 4 carbonatoms;n is an integer selected from the group consisting of 2 and 3; R₂and R₃ are independently selected from the group consisting of hydrogen,alkyl, alkenyl, aralkyl and alkynyl, and m is an integer selected fromthe group consisting of 1 to 4 inclusive; and pharmaceuticallyacceptable, non-toxic acid addition salts thereof.
 2. Compounds of claim1 wherein X' is hydrogen, n is 2 and m is
 1. 3. A compound of claim 2having the formula ##SPC10##
 4. Compounds of claim 1 wherein R₂ and R₃are hydrogen and m is
 1. 5. Compounds of claim 4 wherein n is
 2. 6. Acompound of claim 5 having the formula ##SPC11##
 7. Pharmaceuticallyacceptable, non-toxic acid addition salts of the compounds of claim 4.8. Pharmaceutically acceptable, non-toxic acid addition salts of thecompounds of claim
 5. 9. Pharmaceutically acceptable, non-toxic acidaddition salts of the compounds of claim
 6. 10. Compounds having theformula ##SPC12##wherein X and X' are defined as in claim 11; n is aninteger selected from the group consisting of 2 and 3; Alk is alkyl; andm is an integer selected from the group consisting of 1 to 4inclusiveand pharmaceutically acceptable, non-toxic acid addition saltsthereof.
 11. Compounds of claim 10 wherein n is 2 and m is
 1. 12. Acompound of claim 11 having the formula ##SPC13##
 13. Compounds havingthe formula ##SPC14##wherein R₂ is lower alkyl.
 14. N-alkyl andN,N'-dialkyl derivatives of compounds of claim
 13. 15. Pharmaceuticallyacceptable, non-toxic acid addition salts of the compounds of claim 14.16. Pharmaceutically acceptable, non-toxic acid addition salts ofcompounds of claim
 13. 17. Compounds of claim 13 wherein R₂ is methyl.18. A compound of claim 17 having the formula ##SPC15## 19.α,N-Dimethyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine. 20.α,α,α'-Tetrafluoroethylene-2,2'-bis (benzylamine). 21.N,N-Dimethyl-3-(α,α,β,β-tetrafluorophenethyl)-o-xylene-α,α'-diamine. 22.N,N,-Dibenzyl-3-(α,.alpha.,β,β-tetrafluorophenethyl)-o-xylene-α,α'-diamine23. 2-Methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzylamine. 24.4-(α,α,β,β-Tetrafluorophenethyl)-benzylamine. 25.α-Methyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine. 26.4-(.alpha.,α,β,β-Tetrafluorophenethyl)-α,α,N-trimethylbenzylamine. 27.4-(.alpha.,α,β,β-Tetrafluorophenethyl)-α,α,N,N-tetramethylbenzylamine.28.4-(p-Methyl-α,α,β,β-tetrafluorophenethyl)-α,α,N-trimethylbenzylamine.